Synthesis of functionalized isoindolinones: Addition of in situ generated organoalanes to acyliminium ions

Article abstract of DOI:10.1016/j.jorganchem.2007.05.035

Addition of in situ generated di- or trisubstituted alkenylalanes to N-acyliminium ions provides rapid access to functionalized isoindolinones. Subsequent ring closing metathesis leads to tricyclic products. These transformations proceed under mild condit

Full text of DOI:10.1016/j.jorganchem.2007.05.035

Journal of Organometallic Chemistry 692 (2007) 4618–4629
www.elsevier.com/locate/jorganchem
Synthesis of functionalized isoindolinones: Addition of in situ generated
organoalanes to acyliminium ions
*
Joshua G. Pierce, David L. Waller, Peter Wipf
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 26 March 2007; received in revised form 20 May 2007; accepted 21 May 2007
Available online 2 June 2007
Dedicated to Prof. Gerhard Erker in celebration of his 60th birthday and in recognition of his pioneering contributions to transition metal chemistry.
Abstract
Addition of in situ generated di- or trisubstituted alkenylalanes to N-acyliminium ions provides rapid access to functionalized isoind-
olinones. Subsequent ring closing metathesis leads to tricyclic products. These transformations proceed under mild conditions and allow
for the convergent synthesis of biologically significant scaffolds from readily available starting materials.
(Me)H
R'
AlMe2
O
O
NR
NR
OPiv
CH2Cl2, rt
H(Me)
R'
O
[Ru]
N
ꢀ 2007 Elsevier B.V. All rights reserved.
Keywords: Isoindolinone; Aluminum; Zirconium; Hydrozirconation; Carbometallation; N-Acyliminium ion
1. Introduction
hypertensive [5], antipsychotic [6], vasodilatory [7] and
antileukemic [8] effects, which renders the development
of new synthetic routes toward these heterocycles particu-
larly attractive. While several methods have been reported
for the preparation of isoindolinones [9], some leading to
the synthesis of natural products [10] and compound
libraries [11], many approaches suffer from a lack of gen-
erality or functional group compatibility.
Isoindolinones constitute the core structures of numer-
ous naturally occurring biologically active compounds
such as magallanesine 1 [1] and lennoxamine 2 [2] as well
as many drug candidates such as pagoclone 3 [3] (Fig. 1).
Isoindolinones demonstrate a remarkably wide array of
biological activities, including anti-inflammatory [4], anti-
In view of the potent and diverse biological spectrum
of isoindolinones, we initiated studies directed at their
preparation as part of our program for the synthesis of
*
Corresponding author.
E-mail address: pwipf@pitt.edu (P. Wipf).
0022-328X/$ - see front matter ꢀ 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2007.05.035

J.G. Pierce et al. / Journal of Organometallic Chemistry 692 (2007) 4618–4629
4619
intermediates [15] and have previously been employed in
the formation of simple isoindolinones [16]; however, with
the exception of allylsilanes, the addition of functionalized
organometallic reagents to these systems has not yet been
exploited. Moreover, the intramolecular addition would
potentially provide an entry toward strained medium-
rings containing (E)-alkenes.
OMe
O
O
MeO
OMe
Me
N
N
O
O
2
O
1
O
O
O
2. Results and discussion
N
N
N
O
Our investigations began with the synthesis of meth-
oxy-8 and phenoxy lactam 9 (Scheme 2). Alcohol 5 was
obtained in 85% yield by the isomerization of the com-
mercially available hept-3-yne-1-ol with KAPA reagent
in 85% yield [17]. Imide 6 could then be constructed by
a Mitsunobu alkylation with alkynol 5, which proceeded
in 82% yield. Reduction with sodium borohydride was
followed by a methanol exchange to give methoxylactam
8 in 40% overall yield (Scheme 1). With the key substrate
in hand, we submitted 8 to our water-accelerated carboa-
lumination conditions (AlMe3 (3 equiv.), H2O (1 equiv.),
zirconocene dichloride (10 mol%)) which only returned
starting material with no evidence for elimination of
methanol or carboalumination of the alkyne moiety
(Scheme 3).
We anticipated the need for a better leaving group and
hence prepared phenoxy lactam 9, which was generated
by treatment of 7 with SOCl2 and catalytic DMF. The
resulting unstable chloride intermediate was immediately
treated with phenol in the presence of triethylamine to yield
9 in 34% yield [18]. When 9 was subjected to the carboalu-
mination conditions, only alkylated lactam 10 (10%), start-
ing material (52%), and decomposition products were
observed by NMR analysis (Scheme 3).
Cl
3
Fig. 1. Biologically active isoindolinones.
Al
Al
R
OMe
N
OMe
A
B
R
n
N
O
N
n
n
n>4
n>4
n>4
O
O
R
C
N
O
R = Me or H
Scheme 1. Proposed intramolecular addition of alkenylalanes to
N-acyliminium ions. (A) Zirconium-catalyzed, water-accelerated carboa-
lumination or hydrozirconation/transmetallation; (B) elimination; (C)
addition/ring closure.
nitrogen containing heterocycles [12]. We initially pro-
posed combining our water-accelerated carboalumina-
tion [13] or hydrozirconation [14] with an intramolecular
N-acyliminium ion addition in a cascade process that
would generate medium-ring containing isoindolinones
(Scheme 1). N-Acyliminium ions are versatile synthetic
These experiments suggested that the functional-
ity present in these lactam acetals was inhibiting the
O
N
O
OH
5
NH
PPh3, DIAD, THF, 82%
O
O
4
6
OH
N
NaBH4, MeOH
O
7
1. SOCl2, DMF (cat.)
MeOH, d,l-CSA
40%
2. PhOH, Et3N, THF; 34%
OMe
OPh
N
N
O
O
9
8
Scheme 2. Synthesis of lactam precursors.

4620
J.G. Pierce et al. / Journal of Organometallic Chemistry 692 (2007) 4618–4629
OR
8, No Reaction
9, 10% 10 + SM
AlMe3 (3 eq)
N
H2O (1 eq)
Cp2ZrCl2 (10 mol%)
CH2Cl2
O
R = Me, 8
R = Ph, 9
N
O
10
Scheme 3. Attempted cascade cyclization of 8 and 9.
carboalumination step. We postulated that the lactam
group was responsible for the observed inhibition, as
highly Lewis basic functionality has been noted to
decrease the reactivity of aluminoxanes [19]. Therefore,
we performed a series of GC experiments to test this
hypothesis with 1-heptyne, which is known to undergo
O
O
Cp2ZrHCl, then
Me3Al, rt, 0.01 M
N
N
R
12
8, R = OMe
11, R = OPiv
rapid water-accelerated carboalumination.
A control
Scheme 5. Attempted hydrozirconation and medium-ring formation.
experiment demonstrated that the carboalumination of
heptyne with AlMe3 (3 equiv.), H2O (1 equiv.), and
Cp2ZrCl2 (10 mol%) proceeded to completion in less than
5 min at low temperatures (À78 ꢁC to À25 ꢁC) to furnish
a 97:3 mixture of regioisomers by GC analysis (Scheme
4). Conducting the identical experiment in the presence
of 1 equiv. of methoxylactam 8 dramatically inhibited car-
boalumination, with only 4.4% of heptyne undergoing
conversion after 1 h at ambient temperature. Most likely,
this inhibition is due to the coordination of Lewis basic
functional groups to AlMe3 oligomers, thus preventing
alkyne carboalumination.
Due to the lack of reactivity in the carboalumination
approach, we turned to hydrozirconation, known to be
quite tolerant of diverse functionality [14]. When lactam
8 was treated with Cp2ZrHCl, only the corresponding
alkene was recovered (Scheme 5). Treatment of the inter-
mediate alkenylzirconocene with AgClO4 or trimethylalu-
minum also provided no desired cyclization products.
Our attempts to enhance leaving group ability by using
pivaloate 11 also failed to promote cyclization under any
of the above conditions. Highly concentrated reaction mix-
tures or prolonged heating resulted only in slow methyl
group addition. Possibly, the ring strain present in the
desired products is too high to allow the reaction to pro-
ceed under these experimental conditions.
Because the intramolecular cyclizations proved elusive,
we turned our attention toward an alternative construction
of these systems starting with an intermolecular addition
process. Alkenylation of N-acyliminium ions can often
require harsh reaction conditions [20] or unusual anomeric
leaving groups [21]; a noteworthy exception is the mild
intermolecular addition of alkenyl boronates reported by
Batey et al. [22] We first explored the hydrozirconation of
terminal alkynes as a method to generate alkenyl nucleo-
philes (Table 1). Hydrozirconation of 1-hexyne, followed
by treatment with silver perchlorate [23] and lactam 13
yielded only a trace of addition product after 24 h at r.t.
(entry 1, Table 1). Transmetallation to dimethylzinc also
proved unsuccessful (entry 2, Table 1). Gratifyingly,
AlMe3, H2O
+
Cp2ZrCl2
-78 oC to rt
100% in <5 min
97:3
AlMe3, H2O
Cp2ZrCl2
4.4% after 60 min
OMe
N
5
8
O
-78 oC to rt
Scheme 4. GC analysis of the water-accelerated carboalumination of heptyne in the presence and absence of 8.

J.G. Pierce et al. / Journal of Organometallic Chemistry 692 (2007) 4618–4629
4621
Table 1
Table 2
Reaction optimization for the addition of hexenylzirconocene to lactams
Variation of alkyne substrates
O
13–15
O
Me3Al, rt
Cp2ZrHCl
NBn
R
NBn
O
O
CH2Cl2
Cp2ZrHCl
CH2Cl
R
13-15
NBn
NBn
OPiv
C4H9
R
Conditions
2
15
17
C4H9
Entry
R (alkyne)
Product [%]
Entry
Conditions
R (lactam acetal)
17 [%]
1
2
3
4
C4H9 (16)
c-C6H11 (18)
CH2CH2OTBDPS (20)
CH2CH2N(CO2Me)Ts (22)
17 [81]
19 [79]
21 [71]
23 [62]
1
2
3
4
5
6
a
AgClO4, 24 h, r.t.
Me2Zn, 12 h, r.t.
Me3Al, 12 h, r.t.
Me3Al, 4 h, r.t.
Me3Al, 4 h, r.t.
AgClO4, 12 h, r.t.
OMe (13)
OMe (13)
OMe (13)
OAc (14)
OPiv (15)
OPiv (15)
Tracea
–
43b
30
81
Complex mixture
1. Cp2ZrHCl, CH2Cl2
Product was formed as a mixture of alkene isomers.
Starting material observed after 12 h.
O
2.
b
NBn
O
hydrozirconation-transmetallation to trimethylaluminum
[24] generated an alkenylalane that reacted with lactam
13 in a moderate 43% yield (entry 3, Table 1). We further
increased the leaving group ability by using acetate 14;
however, product 17 was only formed in 30% yield while
the remaining starting material was consumed (entry 4,
Table 1). Attempts to perform this reaction in THF or tol-
uene led to recovered starting material. In an effort to pre-
vent decomposition pathways while retaining good leaving
group ability, pivaloate 15 was synthesized and treated
with the in situ generated alane to provide hexenyl isoind-
olinone 17 in 81% yield without any observed isomeriza-
tion of the alkene moiety (entry 5, Table 1). Attempts to
achieve this transformation under cationic conditions with
silver perchlorate [20] led to complex mixtures, seemingly
arising from alkene isomerization. The mild conditions
under which the addition proceeds and the ability to utilize
readily available alkynes and pivaloate iminium ion precur-
sors encouraged us to explore this process further.
Among the numerous methods known for the synthesis
of substituted isoindolinones, only a few examples of Heck-
type cyclizations install an alkenyl moiety at the 3-position
[25]. The modularity of our approach warranted further
investigation, and therefore we evaluated the substrate
scope of this process. As shown in Table 2, silyl ether, car-
bamate, and sulfonamide functionalities are well tolerated,
generating functionalized isoindolinones in a high yielding,
one-pot procedure.
OPiv
25
NBn
C4H9
Me3Al, rt
83%
26
C4H9
Scheme 6. Addition to succinimide-derived iminium ion precursor.
alkenylalane under our water-accelerated conditions, fol-
lowed by addition of 15, provided isoindolinones 27 and
29 in 77% yield after only 15 min (Table 3). The flexibility
and mild nature of these transformations are well suited for
their application in the synthesis of biologically interesting
target molecules and libraries.
Since this strategy provided a rapid access toward alke-
nyl-functionalized phthalimides, we sought to revisit our
initial goal of generating medium-rings. As a model system,
we synthesized alkyne 30 and allyl-pivaloate 31 and sub-
jected them to our hydrozirconation-transmetallation con-
ditions to generate 32 in 55% yield accompanied by
considerable amounts of methyl addition side product
(Scheme 7). It should be noted that carbometallation of
30 failed and the rate of addition for the alkenylalane gen-
erated via the transmetallation reaction was diminished due
to the presence of the ether functionality. With 32 in hand,
we screened conditions to form the desired 12-membered
macrocycle. Although ring closing metathesis methodology
[23] has been demonstrated to perform well for the synthe-
sis of a variety of macrocycles [26], rapid formation of the
five-membered ring 33 was observed (Scheme 7) [27].
Increasing dilution, change of metathesis catalyst, addition
of Ti(OiPr)4 [28], or varying solvents did not influence the
reaction pathway.
To further probe the scope of this reaction, we synthe-
sized succinimide-derived pivaloate 25 from 1-benzyl-3,3-
dimethylpyrrolidine-2,5-dione (24) and subjected it to our
optimized conditions (Scheme 6). Addition product 26
was isolated in 83% yield. This success bodes well for the
extension of the cyclic iminium ion alkenylation methodol-
ogy toward a broad class of heterocyclic electrophiles.
We also explored the use of trisubstituted alkenes in this
transformation. Although the lactam functionality had
prevented an intramolecular addition, pre-forming the
Due to the ease of formation of pyrrolizidine 33, we
explored the synthesis of this compound via addition of
hexyne to 31 and subsequent ring closing metathesis to pro-
vide tricycle 33 in 75% yield (Scheme 8). Extension of this
approach to the synthesis of fused azepines was achieved

4622
J.G. Pierce et al. / Journal of Organometallic Chemistry 692 (2007) 4618–4629
Table 3
Water-accelerated carboalumination – addition to lactam 15
O
O
NBn
OPiv
15
Me3Al,Cp2ZrCl2
H2O
NBn
R
R
Entry
R
Product [%]
1
2
a
C4H9 (16)
Ph (28)
27 [77]
29 [77]a
Product contains ꢀ5% of a carbometallation regioisomer.
MesN
Cl
NMes
O
Ru
O
O
N
Cl
Ph
PCy3
Cp2ZrHCl; Me3Al
N
N
O
O
O
; 55%
61%
then
33
30
32
O
N
not observed
Ph
OPiv
31
Ph
Scheme 7. Attempted medium-ring formation via ring closing metathesis.
MesN
Cl
NMes
Ph
O
Ru
Cl
N
O
O
N
PCy3
OPiv
N
Cp2ZrHCl
CH2Cl2
31
CH2Cl2
75%
C4H9
Me3Al, rt
73%
34
33
C4H9
O
MesN
Cl
NMes
Ph
N
Ru
O
N
O
Cl
OPiv
PCy3
Cp2ZrHCl
CH2Cl2
36
N
C4H9
Ti(OiPr)4
toluene
67%
Me3Al, rt
72%
37
38
Scheme 8. Application of ring closing metathesis to generate five- and seven-membered fused ring systems.
from indolinone 37, prepared from 2-(pent-4-enyl)isoindo-
line-1,3-dione (35) via pivaloate 36 and 1-hexyne in 72%
yield. Ring closing metathesis of 37 proved to be problem-
atic in CH2Cl2 with several ruthenium catalysts, yielding
only starting material or decomposition products. Addition
of Ti(OiPr)4 in toluene at room temperature resolved these
issues and yielded 67% of 38. Possible deactivation of the
metathesis intermediate by the neighboring amide carbonyl
could explain the difficulty in this transformation [29].
While not fully optimized, these reactions provide proof
of concept for the conversion of our phthalimide substrates
to structurally diverse tricyclic products.

J.G. Pierce et al. / Journal of Organometallic Chemistry 692 (2007) 4618–4629
4623
3. Conclusions
sequence with a d1 of 3 s, and are tabulated by observed
peak. Mass spectra were obtained on a Micromass Auto-
spec double focusing instrument.
We have demonstrated that in situ generated alkenylal-
anes represent versatile nucleophiles for additions to
N-acyliminium ions. While direct intramolecular cycliza-
tion strategies currently suffer from inhibition of the car-
boalumination reaction by Lewis basic functional groups,
pre-forming alkenylalanes via hydrozirconation–transmet-
allation or carboalumination and subsequent addition to
the lactam acetal substrates yields functionalized isoindoli-
nones. This method applies easily prepared or commercially
available starting materials that provide opportunities for
diversification at numerous points and yields synthetically
useful heterocyclic products in a one-pot transformation.
Further elaboration of the alkenyl heterocycles through
the use of ring closing metathesis leads to tricyclic products
that are common motifs in natural products and drug-like
molecules.
4.2. 2-(Hept-6-ynyl)isoindoline-1,3-dione (6)
A solution of hept-6-yn-1-ol (5) (228 mg, 2.04 mmol),
phthalimide 4 (302 mg, 2.04 mmol), and PPh3 (540 mg,
2.04 mmol) in THF (20 mL) was cooled to 0 ꢁC and trea-
ted with DIAD (403 lL, 2.04 mmol) over 5 min. The reac-
tion mixture was warmed to r.t. and stirred for 6 h. The
solvent was evaporated, the residue was dissolved in
EtOAc/hexanes (1:1, 10 mL) and the solids were filtered
off. The filtrate was concentrated and chromatographed
on SiO2 (EtOAc:hexanes, 1:5) to yield imide 6 (407 mg,
1.69 mmol, 82%) as a colorless oil: IR (neat) 3466, 3283,
2941, 2862, 2115, 1772, 1709, 1615, 1397, 1046,
1
720 cmÀ1; H NMR d 7.84–7.79 (m, 2H), 7.72–7.67 (m,
2H), 3.67 (t, 2H, J = 7.1 Hz), 2.17 (td, 2H, J = 6.8,
2.6 Hz), 1.91 (t, 1H, J = 2.6 Hz), 1.75–1.61 (m, 2H),
1.58–1.51 (m, 2H), 1.49–1.38 (m, 2H); 13C NMR d 168.3
(2C), 133.8 (2C), 132.1 (2C), 123.1 (2C), 84.2, 68.4, 37.7,
28.0, 27.9, 25.8, 18.2; MS (EI) m/z (rel. intensity) 241
([M]+, 11), 186 (6), 173 (10), 160 (100), 148 (31), 130
(29), 104 (27); HRMS (EI) m/z calcd. for C15H15NO2
241.1103, found 241.1107.
4. Experimental
4.1. General details
All reactions were performed under an N2 atmosphere
and all glassware was dried in an oven at 140 ꢁC for 2 h
prior to use. THF and Et2O was distilled over sodium/
benzophenone ketyl, Et3N was distilled from CaH2,
and CH2Cl2 and toluene were purified using an alumina
filtration system. Cp2ZrHCl [30], 18 [31], 20 [32], and 22
[24] were prepared according to literature procedures and
all other compounds were purchased and used as
received.
Reactions were monitored by TLC analysis (EM Sci-
ence pre-coated silica gel 60 F254 plates, 250 mm layer
thickness) and visualization was accomplished with a
254 nm UV light and by staining with a PMA solution
(5 g of phosphomolybdic acid in 100 mL of 95% EtOH),
p-anisaldehyde solution (2.5 mL of p-anisaldehyde, 2 mL
of AcOH, and 3.5 mL of conc. H2SO4 in 100 mL of 95%
EtOH), Vaughn’s reagent (4.8 g of (NH4)6Mo7O24 Æ 4H2O
and 0.2 g of Ce(SO4)2 in 100 mL of a 3.5 N H2SO4 solu-
tion) or a KMnO4 solution (1.5 g of KMnO4 and 1.5 g
of K2CO3 in 100 mL of a 0.1% NaOH solution). Flash
chromatography on SiO2 was used to purify the crude
reaction mixtures.
4.3. 2-(Hept-6-ynyl)-3-methoxyisoindolin-1-one (8)
To a 0 ꢁC solution of imide 6 (40.0 mg, 0.166 mmol) in
MeOH (4 mL) was added NaBH4 (5.00 mg, 0.125 mmol).
The reaction mixture was stirred at r.t. for 2.5 h, quenched
with H2O (1 mL) and the MeOH was removed in vacuo.
The residue was extracted with CH2Cl2 (5 · 3 mL) and
the combined organic layers were washed with brine, dried
(Na2SO4), and concentrated to provide crude hydroxylac-
tam 7 which was immediately dissolved in MeOH (4 mL),
treated with d,l-camphorsulfonic acid (3.85 mg, 0.0166
mmol) and stirred for 16 h. The solvent was removed in
vacuo and the residue was partitioned between H2O
(5 mL) and CH2Cl2 (5 mL). The aqueous layer was
extracted with CH2Cl2 (3 · 5 mL). The combined organic
layers were washed with brine, dried (Na2SO4), concen-
trated and chromatographed on SiO2 (EtOAc:hexanes,
1:4) to yield methoxy lactam 8 (17.0 mg, 0.0661 mmol,
40% over two steps) as a colorless oil: IR (neat) 3298,
Melting points were determined using a Laboratory
Devices Mel-Temp II. Infrared spectra were determined
1
2925, 2854, 2115, 1702, 1466, 1412, 1059, 746 cmÀ1; H
on a Nicolet Avatar 360 FT-IR spectrometer. H and 13C
NMR d 7.84–7.80 (m, 1H), 7.61–7.49 (m, 3H), 5.88 (s,
1H), 3.79 (ddd, 1H, J = 13.7, 8.1, 7.3 Hz), 3.24 (ddd, 1H,
J = 14.0, 8.0, 6.3 Hz), 2.87 (s, 3H), 2.19 (td, 2H, J = 6.7,
2.6 Hz), 1.92 (t, 1H, J = 2.6 Hz), 1.75–1.63 (m, 2H),
1.62–1.43 (m, 4H); 13C NMR d 167.6, 140.3, 133.2, 131.9,
129.9, 123.4 (2C), 86.2, 84.3, 68.4, 49.1, 39.3, 28.0, 27.6,
26.0, 18.3; MS (EI) m/z (rel. intensity) 257 ([M]+, 18),
242 (17), 226 (20), 176 (66), 146 (100), 132 (39), 117 (21);
HRMS (EI) m/z calcd. for C16H19NO2 257.1416, found
257.1419.
1
NMR spectra were obtained on a Bruker Avance 300
instrument in CDCl3 unless otherwise noted. Chemical
shifts were reported in parts per million with the residual
1
solvent peak used as an internal standard. H NMR spec-
tra were run at 300 MHz and are tabulated as follows:
chemical shift, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, p = pentet, m = multiplet), num-
ber of protons, and coupling constant(s). 13C NMR spectra
were run at 76 MHz using a proton-decoupled pulse

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J.G. Pierce et al. / Journal of Organometallic Chemistry 692 (2007) 4618–4629
4.4. 2-(Hept-6-ynyl)-3-phenoxyisoindolin-1-one (9)
3:7) to yield 1.09 g (80% over 2 steps) of 15 as a colorless
solid: m.p. 88.1–89.0 ꢁC (CH2Cl2); IR (neat) 3419, 3062,
3031, 2973, 2934, 2872, 1717, 1408, 1276, 1122, 959,
A 0 ꢁC solution of imide 6 (307 mg, 1.27 mmol) in
MeOH (20 mL) was treated with NaBH4 (36.3 mg,
0.953 mmol), warmed to r.t. and stirred for 1 h. The reac-
tion mixture was quenched with H2O (10 mL) and the
MeOH was removed in vacuo. The residue was extracted
with CH2Cl2 (6 · 10 mL) and the combined organic layers
were washed with brine, dried (Na2SO4) and concentrated
to yield crude hydroxylactam 7 as a colorless oil. A portion
of the crude hydroxylactam (101 mg, 0.416 mmol) was
immediately dissolved in THF (5 mL) at r.t. and treated
with SOCl2 (30.3 lL, 0.416 mmol) and DMF (1 drop)
and stirred for 14 h. The volatiles were removed under
reduced pressure and the residue was dried in vacuo for
12 h. The unstable crude chloride was obtained as a color-
less oil and immediately dissolved in THF (4.1 mL) at
ambient temperature. This solution was treated with phe-
nol (58.0 mg, 0.620 mmol) and Et3N (288 lL, 2.07 mmol)
and stirred for 2 h. The reaction mixture was quenched
with H2O (1 mL) and the THF was removed in vacuo.
The residue was extracted with CH2Cl2 (4 · 5 mL) and
the combined organic layers were washed with brine, dried
(Na2SO4), and concentrated. The residue was chromato-
graphed on SiO2 (EtOAc:hexanes, 1:3) to yield phenoxylac-
tam 9 (45.0 mg, 1.41 mmol, 34% over two steps) as a
colorless oil: IR (neat) 3296, 2936, 2115, 1707, 1588,
1
751 cmÀ1; H NMR d 7.92–7.84 (m, 1H), 7.61–7.53 (m,
2H), 7.50–7.43 (m, 1H), 7.38–7.22 (m, 5H), 6.89 (s, 1H),
5.01 (d, 1H, J = 15 Hz), 4.44 (d, 1H, J = 15 Hz), 1.13 (s,
9H); 13C NMR d 178.4, 167.9, 141.3, 136.8, 132.5, 131.9,
130.2, 128.7, 128.1, 127.7, 123.7, 123.7, 81.0, 44.2, 39.0,
26.8; MS (EI) m/z (rel. intensity) 323 ([M]+, 35), 221
(100), 133 (65), 91 (100); HRMS (EI) m/z calcd. for
C21H23NO 323.1521, found 323.1515.
4.6. (E)-2-Benzyl-3-(hex-1-enyl)isoindolin-1-one (17)
General protocol A. To a solution of 1-hexyne (16)
(60.5 lL, 0.526 mmol) in CH2Cl2 (1.5 mL) was added
zirconocene hydrochloride (156 mg, 0.605 mmol) and the
resulting suspension was stirred at r.t. for 10 min. The
resulting yellow solution was cooled to 0 ꢁC and Me3Al
(1.0 M in CH2Cl2, 0.605 mL, 0.605 mmol) and 15
(85.0 mg, 0.263 mmol) were added. The mixture was
warmed to r.t. and stirred at this temperature for 1 h,
quenched with sat. aq. NH4Cl, and extracted with CH2Cl2.
The organic layers were separated, dried (MgSO4) and con-
centrated. The residue was purified by chromatography on
SiO2 (EtOAc:hexanes, 3:7) to yield 65.1 mg (81%) of 17 as a
colorless oil: IR (neat) 3479, 3031, 2927, 2857, 1694, 1615,
1491, 1415, 1222, 992, 780 cmÀ1
;
1H NMR d 7.85–7.79
1400, 972 cmÀ1; H NMR d 7.91–7.86 (m, 1H), 7.56–7.42
1
(m, 1H), 7.53–7.46 (m, 3H), 7.33–7.27 (m, 2H), 7.08–6.98
(m, 3H), 6.42 (s, 1H), 3.80 (dt, 1H, J = 14.2, 7.4 Hz),
3.44 (ddd, 1H, J = 14.0, 7.8, 6.4 Hz), 2.16 (td, 2H,
J = 6.7, 2.6 Hz), 1.91 (t, 1H, J = 2.6 Hz), 1.78–1.61 (m,
2H), 1.57–1.39 (m, 4H); 13C NMR d 167.4, 156.3, 141.3,
132.3, 132.0, 130.0, 129.7 (2C), 123.5, 123.3, 123.1, 118.1
(2C), 86.8, 84.2, 68.4, 40.0, 27.9, 27.6, 25.9, 18.2; MS (EI)
m/z (rel. intensity) 319 ([M]+, 70), 265 (28), 226 (100),
198 (8), 146 (52), 132 (65); HRMS (EI) m/z calcd. for
C21H21NO2 319.1572, found 319.1573.
(m, 2H), 7.36–7.21 (m, 6H), 5.90 (dt, 1H, J = 15.0,
6.8 Hz), 5.30 (d, 1H, J = 14.8 Hz), 5.09 (dd, 1H, J = 15.2,
9.2 Hz), 4.70 (d, 1H, J = 9.2 Hz), 4.17 (d, 1H,
J = 14.9 Hz), 2.13 (app q, 2 H, J = 6.7 Hz), 1.50–1.30 (m,
4H), 0.94 (t, 3H, J = 7.2 Hz); 13C NMR d 167.9, 145.1,
138.3, 137.5, 131.8, 131.5, 128.6, 128.3, 127.3, 126.1,
123.6, 123.0, 62.7, 43.8, 31.8, 31.1, 22.1, 13.8; MS (EI)
m/z (rel. intensity) 305 ([M]+, 100), 248 (40), 237 (70),
214 (40); HRMS (EI) m/z calcd. for C21H23NO 305.1780,
found 305.1785.
4.5. 2-Benzyl-3-oxoisoindolin-1-yl pivaloate (15)
4.7. (E)-2-Benzyl-3-(2-cyclohexylvinyl)isoindolin-1-one
(19)
To a solution of benzyl phthalimide (8.89 g, 37.5 mmol)
in MeOH (130 mL) was added sodium borohydride (1.42 g,
37.5 mmol) at 0 ꢁC. The resulting reaction mixture was stir-
red at 0 ꢁC for 2 h and carefully quenched with H2O. The
aqueous layer was extracted with EtOAc (2·) and the
organic layer was separated, dried (MgSO4) and concen-
trated. The residue was dried to yield a white solid which
was carried on to the next step without further purification.
To a solution of the crude reduced phthalamide (1.00 g,
4.20 mmol) in THF (30 mL) was added Et3N (1.17 mL,
8.40 mmol) and pivaloyl chloride (621 lL, 5.04 mmol) at
0 ꢁC and the reaction mixture was allowed to warm to
r.t. and stirred at this temperature for 4 h. The mixture
was quenched with sat. aq. NaHCO3, extracted with
EtOAc (2·), dried (MgSO4) and concentrated. The residue
was purified by chromatography on SiO2 (EtOAc:hexanes,
According to general protocol A, alkyne 18 (66.9 mg,
0.618 mmol), CH2Cl2 (1.5 mL), zirconocene hydrochloride
(183 mg, 0.711 mmol), Me3Al (1.0 M in CH2Cl2, 0.711 mL,
0.711 mmol) and 15 (100 mg, 0.309 mmol) afforded
80.8 mg (79%) of 19 as a colorless oil after purification
on SiO2 (EtOAc:hexanes, 3:7): IR (neat) 3375, 3030,
1
2921, 2851, 2243, 1220, 1200, 1097, 844 cmÀ1; H NMR d
7.92–7.86 (m, 1 H), 7.54–7.41 (m, 2H), 7.35–7.20 (m, 6H),
5.85 (dd, 1H, J = 15.3, 6.6 Hz), 5.28 (d, 1H, J = 14.8 Hz),
5.02 (ddd, 1H, J = 15.3, 9.2, 1.2 Hz), 4.67 (d, 1H,
J = 9.2 Hz), 4.18 (d, 1H, J = 14.8 Hz), 2.14–1.96 (m, 1H),
1.85–1.60 (m, 4H), 1.42–1.00 (m, 6H); 13C NMR d 167.9,
145.1, 144.1, 137.4, 131.8, 131.4, 128.5, 128.3, 128.2,
127.3, 123.6, 122.9, 62.8, 43.8, 40.3, 32.6, 26.0, 25.8; MS
(EI) m/z (rel. intensity) 331 ([M]+, 86), 248 (40), 237

J.G. Pierce et al. / Journal of Organometallic Chemistry 692 (2007) 4618–4629
4625
(100); HRMS (EI) m/z calcd. for C23H25NO 331.1936,
found 331.1951.
135.8, 128.3, 128.1, 127.5, 43.2, 42.0, 39.7, 25.1; MS (EI)
m/z (rel intensity) 217 ([M]+, 100), 174 (33), 133 (22);
HRMS (EI) m/z calcd. for C13H15NO2 217.1103, found
217.1104.
4.8. (E)-2-Benzyl-3-(4-(tert-butyldiphenylsilyloxy)but-1-
enyl)isoindolin-1-one (21)
4.11. 1-Benzyl-4,4-dimethyl-5-oxopyrrolidin-2-yl pivaloate
(25)
According to general protocol A, alkyne 20 (94.4 mg,
0.306 mmol), CH2Cl2 (1 mL), zirconocene hydrochloride
(78.9 mg, 0.306 mmol), Me3Al (1.0 M in CH2Cl2,
0.306 mL, 0.306 mmol) and 15 (50.0 mg, 0.153) afforded
57.6 mg (71%) of 21 as a colorless oil after purification
on SiO2 (EtOAc:hexanes, 2:8): IR (neat) 3450, 2930,
A solution of imide 24 (1.14 g, 5.25 mmol) in MeOH
(53 mL) was treated with NaBH4 (200 mg, 2.62 mmol) at
ambient temperature. After 6 h, the reaction mixture was
concentrated, the residue dissolved in CH2Cl2 (50 mL)
and treated with sat. aq. NH4Cl. The aqueous layer was
separated and washed with CH2Cl2 (2·) and the combined
organic layers were dried (MgSO4), filtered, concentrated
and the resulting oil used without further purification. A
solution of the crude oil in CH2Cl2 (50 mL) was treated
sequentially with Et3N (2.19 mL, 15.7 mmol, 3 equiv.),
DMAP (128 mg, 1.05 mmol, 20 mol %) and pivaloyl
chloride (1.29 mL, 10.5 mmol, 2 equiv.) at ambient temper-
ature. After 6 h, the reaction mixture was quenched with
3 M HCl and the aqueous layer washed with CH2Cl2
(3·). The combined organic layers were washed with
H2O, dried (MgSO4), filtered, and concentrated. The resi-
due was purified by chromatography on SiO2 (EtOAc:hex-
anes, 1:2) to yield 398 mg (25%) of 25 as a colorless oil: IR
2857, 1692, 1428, 1111, 735, 701 cmÀ1 1H NMR d
;
7.92–7.86 (m, 1H), 7.72–7.65 (m, 4H), 7.53–7.35 (m,
9H), 7.32–7.21 (m, 5H), 5.96 (dt, 1H, J = 15.3, 6.8 Hz),
5.27 (d, 1H, J = 14.9 Hz), 5.16 (dddd, 1H, J = 15.3,
9.1, 1.2, 1.2 Hz), 4.71 (d, 1H, J = 9.1 Hz), 4.16 (d, 1H,
J = 14.9 Hz), 3.77 (dt, 2H, J = 6.3, 1.2 Hz), 2.37 (app
q, 2H, J = 6.6 Hz), 1.08 (s, 9H); 13C NMR d 168.0,
144.9, 137.5, 135.6, 134.8, 133.8, 131.9, 131.5, 129.7,
128.6, 128.4, 128.2, 127.7, 127.4, 123.6, 123.1, 63.2,
62.6, 43.9, 35.6, 26.9, 19.2; MS (EI) m/z (rel. intensity)
532 ([M]+, 35), 488 (100), 474 (45), 306 (65), 252 (75);
HRMS (EI) m/z calcd. for C35H37NO2Si 532.2664, found
532.2664.
1
4.9. (E)-Methyl 4-(2-benzyl-3-oxoisoindolin-1-yl)but-3-
enyl(tosyl)carbamate (23)
(neat) 2971, 1710, 1419, 1125, 707 cmÀ1; H NMR d 7.33–
7.21 (m, 5H), 5.99 (d, 1H, J = 6.3 Hz), 4.74 (d, 1H,
J = 14.7 Hz), 4.15 (d, 1H, J = 14.7 Hz), 2.14 (dd, 1H,
J = 14.1, 6.3 Hz), 1.87 (d, 1H, J = 14.4 Hz), 1.32 (s, 3H),
1.22 (s, 3H), 1.10 (s, 9H); 13C NMR d 180.6, 177.9,
136.6, 128.7, 128.2, 127.6, 82.1, 44.8, 41.5, 39.3, 38.7,
26.8, 26.5, 25.6; MS (EI) m/z (rel. intensity) 303 ([M]+,
36), 275 (15), 202 (85), 158 (46); HRMS (EI) m/z calcd.
for C18H25NO3 303.1834, found 303.1827.
According to general protocol A, alkyne 22 (174 mg,
0.618 mmol), CH2Cl2 (1.5 mL), zirconocene hydrochloride
(183 mg, 0.711 mmol), Me3Al (1.0 M in CH2Cl2,
0.711 mL, 0.711 mmol) and 15 (100 mg, 0.309) afforded
95.1 mg (62%) of 23 as a colorless oil after purification on
SiO2 (acetone:CH2Cl2, 0.3:9.7): IR (neat) 3467, 3032, 2957,
1
2245, 1735, 1686, 1359, 1168, 733 cmÀ1; H NMR d 7.92–
7.78 (m, 3H), 7.56–7.41 (m, 2H), 7.39–7.18 (m, 9H), 5.93
(dt, 1H, J = 15.2, 7.0 Hz), 5.26 (d, 1H, J = 14.9 Hz), 5.21
(dd, 1H, J = 15.1, 9.1 Hz), 4.73 (d, 1H, J = 9.0), 4.18 (d,
1H, J = 14.9 Hz), 3.95 (t, 2H, J = 7.0 Hz), 3.69 (s, 3H),
2.58 (app q, 2 H, J = 7.0 Hz), 2.43 (s, 3H); 13C NMR d
168.0, 152.8, 144.8, 144.6, 137.4, 136.5, 133.0, 131.7, 131.6,
129.7, 129.4, 128.6, 128.3, 128.3, 127.4, 123.6, 123.2, 62.3,
53.8, 46.5, 43.8, 32.9, 21.6; MS (EI) m/z (rel. intensity) 504
([M]+, 50), 262 (40), 155 (100); HRMS (EI) m/z calcd. for
C28H28N2O5S 504.1719, found 504.1724.
4.12. (E)-1-Benzyl-5-(hex-1-enyl)-3,3-dimethylpyrrolidin-
2-one (26)
According to general protocol A, hexyne (16) (9.77 mg,
0.119 mmol), CH2Cl2 (1 mL), zirconocene hydrochloride
(30.7 mg, 0.119 mmol), Me3Al (1.0 M in CH2Cl2,
0.119 mL, 0.119 mmol) and 25 (18.0 mg, 0.0593 mmol)
afforded 14.0 mg (83%) of 26 as a colorless oil after purifi-
cation on SiO2 (EtOAc:hexanes, 2.5:7.5): IR (neat) 2958,
1
2928, 2868, 1692, 1411, 1262, 972, 752 cmÀ1; H NMR d
7.35–7.23 (m, 3H), 7.21–7.13 (m, 2H), 5.53 (dt, 1H,
J = 15.0, 6.6 Hz), 5.16 (dd, 1H, J = 15.3, 9.0 Hz), 4.94 (d,
1H, J = 14.4 Hz), 3.88 (d, 1H, J = 14.4 Hz), 3.73 (app q,
1H, J = 7.8 Hz), 2.10–1.98 (m, 2H), 1.99 (dd, 1H,
J = 12.9, 7.2 Hz), 1.58 (dd, 1H, J = 12.9, 8.1 Hz), 1.42–
1.28 (m, 4H), 1.24 (s, 3H), 1.11 (s, 3H), 0.92 (t, 3H,
J = 6.9 Hz); 13C NMR d 179.6, 137.2, 135.8, 129.8, 128.4,
128.3, 127.2, 56.9, 44.2, 42.0, 40.3, 31.8, 31.2, 25.5, 24.7,
22.2, 13.9; MS (EI) m/z (rel. intensity) 285 ([M]+, 20),
228 (20), 175 (30), 91 (100); HRMS (EI) m/z calcd. for
C19H27NO 285.2093, found 285.2090.
4.10. 1-Benzyl-3,3-dimethylpyrrolidine-2,5-dione (24)
A mixture of 2,2-dimethylsuccinic anhydride (710 mg,
5.55 mmol) and benzyl amine (712 mg, 6.66 mmol,
1.2 equiv.) was heated over a bunsen burner for ꢀ1 min.
The cooled mixture was purified by chromatography on
SiO2 (EtOAc:hexanes, 1:1) to furnish 1.14 g (95%) of 24
as a colorless oil: IR (neat) 2969, 2933, 1777, 1702, 1344,
1
1142, 709 cmÀ1; H NMR d 7.29–7.21 (m, 5H), 4.57 (s,
2H), 2.47 (s, 2H), 1.22 (s, 6H); 13C NMR d 182.5, 175.1,

4626
J.G. Pierce et al. / Journal of Organometallic Chemistry 692 (2007) 4618–4629
4.13. (E)-2-Benzyl-3-(2-methylhex-1-enyl)isoindolin-1-one
(27)
and concentrated. The residue was purified by chromatog-
raphy on SiO2 (EtOAc:hexanes, 1:9) to yield 9.00 g (69%)
of 30 as a colorless oil: IR (neat) 3298, 3027, 2951, 2854,
1
General protocol B. To a À30 ꢁC solution of AlMe3
(89.0 mg, 1.24 mmol) and Cp2ZrCl2 (9.00 mg, 0.0309
mmol) in CH2Cl2 (1.5 mL) was added H2O (11.1 mg,
0.619 mmol) dropwise. The reaction mixture was warmed
to ambient temperature, cooled to 0 ꢁC, treated with
1-hexyne (16) (71.0 lL, 0.619 mmol), stirred for 30 min
and treated with 15 (100 mg, 0.309 mmol). The reaction
mixture was warmed to r.t. and stirred at this temperature
for 1 h, quenched with sat. aq. NH4Cl, and extracted
with CH2Cl2. The organic layers were separated, dried
(MgSO4) and concentrated. The residue was purified by
chromatography on SiO2 (EtOAc:hexanes, 3:7) to yield
76.0 mg (77%) of 27 as a colorless oil: IR (neat) 2956,
2117, 1478, 1365, 1111, 967 cmÀ1; H NMR d 7.44-7.37
(m, 2H), 7.37–7.27 (m, 2H), 7.27–7.21 (m, 1H), 6.62 (d,
1H, J = 15.9Hz), 6.30 (dt, 1H, J = 15.9, 6.0), 4.15 (dd,
2H, J = 6.0, 0.9 Hz), 3.60 (t, 2 H, J = 6.3 Hz), 2.34 (dt,
2H, J = 7.2, 2.7 Hz), 1.96 (t, 1H, J = 2.7 Hz), 1.85 (app
p, 2H, J = 6.6 Hz); 13C NMR d 136.5, 131.8, 128.3,
127.4, 126.2, 126.0, 83.7, 71.2, 68.5, 68.3, 28.5, 15.1; MS
(EI) m/z (rel. intensity) 199 ([M]+, 100), 186 (35), 173
(35), 131 (100); HRMS (EI) m/z calcd. for C14H16O
199.1123, found 199.1126.
4.16. 2-Allyl-3-oxoisoindolin-1-yl pivaloate (31)
1
2929, 2858, 1694, 1468, 1401, 749, 703 cmÀ1; H NMR d
To a solution of 2-allylisoindoline-1,3-dione (3.64 g,
19.4 mmol) in MeOH (100 mL) was added sodium borohy-
dride (734 mg, 19.4 mmol) at 0 ꢁC. The resulting reaction
mixture was stirred at 0 ꢁC for 2 h and carefully quenched
with H2O. The aqueous layer was extracted with EtOAc
(2·) and the organic layer was separated, dried (MgSO4)
and concentrated. The residue was dried to yield a white
solid which was carried on to the next step without further
purification. To a solution of the crude reduced phthalamide
(3.60 g, 19.0 mmol) in THF (100 mL) was added Et3N
(7.90 mL, 57.0 mmol) and pivaloyl chloride (2.81 mL,
22.8 mmol) at 0 ꢁC and the reaction mixture was allowed
to warm to r.t. and stirred at this temperature for 4 h. The
mixture was quenched with sat. aq. NaHCO3, extracted
with EtOAc (2x), dried (MgSO4) and concentrated. The
residue was purified by chromatography on SiO2
(EtOAc:hexanes, 2.5:7.5) to yield 4.40 g (83% over 2 steps)
of 31 as a colorless oil: IR (neat) 2976, 1716, 1405, 1135,
7.89–7.50 (m, 1H), 7.53–7.40 (m, 2H), 7.35–7.20 (m, 6H),
5.31 (d, 1H, J = 14.9 Hz), 5.06 (d, 1H, J = 9.8), 4.81 (dq,
1H, J = 9.8, 1.2 Hz), 4.09 (d, 1H, J = 14.9 Hz), 2.07 (t,
2H, J = 7.1 Hz), 1.67 (d, 3H, J = 1.3 Hz), 1.50–1.22 (m,
4H), 0.91 (t, 3H, J = 7.2 Hz); 13C NMR d 168.1, 145.7,
143.4, 137.5, 132.0, 131.4, 128.5, 128.2, 128.0, 127.3,
123.6, 122.8, 120.6, 57.9, 43.9, 39.3, 29.8, 22.2, 16.5, 13.8;
MS (EI) m/z (rel. intensity) 319 ([M]+, 100), 221 (40);
HRMS (EI) m/z calcd. for C22H25NO 319.1936, found
319.1921.
4.14. (E)-2-Benzyl-3-(2-phenylprop-1-enyl)isoindolin-1-one
(29)
According to general protocol B, alkyne 28 (68.0 lL,
0.619 mmol), AlMe3 (89.0 mg, 1.24 mmol), Cp2ZrCl2
(9.00 mg, 0.0309 mmol), CH2Cl2 (1.5 mL), H2O (11.1 mg,
0.619 mmol) and 15 (100 mg, 0.309 mmol) afforded
81.0 mg (77%) of 29 as a colorless oil and a 95:5 mixture
of regioisomers after purification on SiO2 (EtOAc:hexanes,
1:3): Major isomer: IR (neat) 3030, 2918, 1693, 1602, 1432,
1
753 cmÀ1; H NMR d 7.88–7.80 (m, 1H), 7.62–7.46 (m,
3H), 6.99 (s, 1H), 5.94–5.77 (m, 1H), 5.29–5.15 (m, 2H),
4.44 (dd, 1H, J = 15.9, 5.1 Hz), 3.88 (dd, 1H, J = 15.3,
6.6 Hz), 1.23 (s, 9H); 13C NMR d 178.3, 167.5, 141.2,
132.4, 132.4, 131.8, 130.0, 123.6, 123.5, 118.0, 80.9, 42.8,
39.0, 26.9; MS (EI) m/z (rel. intensity) 273 ([M]+, 60), 172
(100); HRMS (EI) m/z calcd. for C16H19NO3 273.1365,
found 273.1358.
1
1400, 1250, 749 cmÀ1; H NMR d 7.93 (dd, 1H, J = 6.3,
2.1 Hz), 7.54–7.46 (m, 2H), 7.35–7.26 (m, 11H), 5.41 (dd,
1H, J = 9.6, 0.9 Hz), 5.35 (d, 1H, J = 15.0 Hz), 5.27 (d,
1H, J = 9.9 Hz), 4.21 (d, 1H, J = 15.0 Hz), 2.12 (d, 3H,
J = 0.9 Hz); 13C NMR d 168.1, 145.0, 142.0, 141.3, 137.4,
132.0, 131.6, 128.6, 128.3, 127.8, 127.5, 125.8, 123.8,
123.7, 122.9, 58.2, 44.3, 16.3; MS (EI) m/z (rel. intensity)
339 ([M]+, 41), 248 (47), 234 (77), 91 (100); HRMS (EI)
m/z calcd. for C24H21NO 339.1623, found 339.1631. Minor
isomer (characteristic peaks): 1H NMR d 1.44 (d, 3H,
J = 6.9 Hz); 13C NMR d 128.0, 121.9, 18.0.
4.17. 2-Allyl-3-((E)-5-(cinnamyloxy)pent-1-
enyl)isoindolin-1-one (32)
According to general protocol A, alkyne 30 (733 mg,
3.66 mmol), CH2Cl2 (10 mL), zirconocene hydrochloride
(944 mg, 3.66 mmol), Me3Al (1.0 M in CH2Cl2, 3.66 mL,
3.66 mmol) and 31 (500 mg, 1.83 mmol) (reaction time
increased to 12 h) afforded 376 mg (55%) of 32 as a color-
less oil after purification on SiO2 (acetone:CH2Cl2, 0.7:9.3):
IR (neat) 2924, 2853, 1694, 1468, 1289, 1098, 968,
4.15. (E)-(3-(Pent-4-ynyloxy)prop-1-enyl)benzene (30)
To a solution of 4-pentyn-1-ol (4.03 mL, 43.3 mmol) in
hexanes (75 mL) was added 50% NaOH (75 mL), TBAI
(801 mg, 2.17 mmol) and cinnamyl bromide (8.97 g,
45.5 mmol). The reaction mixture was rapidly stirred for
10 h. The organic layer was separated, dried (MgSO4)
1
746 cmÀ1; H NMR d 7.85 (d, 1H, J = 6.6 Hz), 7.57–7.20
(m, 8H), 6.61 (d, 1H, J = 15.9 Hz), 6.29 (dt, 1H,
J = 15.9, 6.0 Hz), 6.02 (dt, 1H, J = 13.8, 6.9 Hz), 5.90–
5.73 (m, 1 H), 5.25–5.07 (m, 3H), 4.87 (d, 1H,

J.G. Pierce et al. / Journal of Organometallic Chemistry 692 (2007) 4618–4629
4627
J = 9.0 Hz), 4.60 (ddd, 1H, J = 15.6, 4.5, 2.7 Hz), 4.15 (dd,
2H, J = 6.0, 1.2 Hz), 3.70 (dd, 1H, J = 15.3, 7.2 Hz), 3.53
(t, 2H, J = 6.3 Hz), 2.25 (app q, 2H, J = 6.9 Hz), 1.77
(app p, 2H, J = 7.8 Hz); 13C NMR d 167.7, 144.9, 137.2,
136.6, 133.2, 132.3, 131.8, 131.4, 128.5, 128.3, 127.6,
126.7, 126.4, 126.1, 123.5, 122.9, 117.5, 71.5, 69.4, 62.9,
42.5, 29.2, 28.9; MS (ESI) m/z (rel. intensity) 396
([M + Na]+, 100), 307 (20), 297 (20); HRMS (ESI) m/z
calcd. for C25H27NO2Na 396.1939, found 396.1928.
EtOAc/hexanes (1:1, 100 mL) and the solids were filtered
off. The filtrate was concentrated and chromatographed
on SiO2 (EtOAc:hexanes, 1:5) to yield 6.44 g (88%) of
imide 35 as a colorless oil: IR (neat) 3466, 3077, 2939,
1773, 1641, 1397, 995, 720 cmÀ1 1H NMR d 7.88–7.81
;
(m, 2H), 7.76–7.67 (m, 2H), 5.90–5.73 (m, 1H), 5.12–4.94
(m, 2H), 3.70 (dt, 2H, J = 7.5, 4.5 Hz), 2.20–2.07 (m,
2H), 1.87–1.73 (m, 2H); 13C NMR d 168.1, 137.1, 133.7,
131.9, 122.9, 115.1, 37.3, 30.8, 27.4; MS (EI) m/z (rel. inten-
sity) 215 ([M]+, 45), 173 (70), 160 (100), 148 (80), 130 (80),
104 (90); HRMS (EI) m/z calcd. for C13H13NO2 215.0946,
found 215.0946.
4.18. 3H-Pyrrolo[2,1-a]isoindol-5(9bH)-one (33)
To a solution of 32 (41.7 mg, 0.112 mmol) in CH2Cl2
(6 mL) was added Grubbs 2nd generation catalyst
(4.75 mg, 5.60 lmol) and the red solution was heated at
50 ꢁC for 1 h, cooled to r.t. and concentrated. The residue
was purified by chromatography on SiO2 (acetone:CH2Cl2,
0.4:9.6) to yield 11.7 mg (61%) of 33 as a colorless oil: IR
4.21. 3-Oxo-2-(pent-4-enyl)isoindolin-1-yl pivalate (36)
To a solution of imide 35 (4.42 g, 20.5 mmol) in MeOH
(100 mL) was added sodium borohydride (776 mg,
20.5 mmol) at 0 ꢁC. The resulting reaction mixture was
stirred at 0 ꢁC for 2 h and carefully quenched with H2O.
The aqueous layer was extracted with EtOAc (2·) and
the organic layer was separated, dried (MgSO4) and con-
centrated. The residue was dried to yield a white solid
which was carried on to the next step without further
purification. To a solution of the crude reduced phthala-
mide (4.23 g, 19.5 mmol) in THF (100 mL) was added
Et3N (8.15 mL, 58.5 mmol), pivaloyl chloride (3.61 mL,
29.3 mmol) and DMAP (119 mg, 0.975 mmol) at 0 ꢁC
and the reaction mixture was allowed to warm to r.t.
and stirred at this temperature for 8 h. The mixture was
quenched with sat. aq. NaHCO3, extracted with EtOAc
(2·), dried (MgSO4) and concentrated. The residue was
purified by chromatography on SiO2 (EtOAc:hexanes,
1:5) to yield 4.70 g (76% over 2 steps) of 36 as a colorless
oil: IR (neat) 3077, 2974, 2873, 1739, 1641, 1618, 1369,
1
(neat) 2872, 1614, 1468, 1395, 1366, 1080, 746 cmÀ1; H
NMR (acetone-d6) d 7.74-7.66 (m, 2H), 7.66–7.58 (m, 1
H), 7.54–7.45 (m, 1H), 6.28–6.20 (m, 1H), 6.08–5.99 (m,
1H), 5.53 (app d, 1H, J = 1.8 Hz), 4.57–4.43 (m, 1H),
3.98–3.83 (m, 1H); 13C NMR (acetone-d6) d 175.4, 148.4,
133.6, 133.1, 131.9, 129.4, 129.2, 124.6, 124.0, 71.1, 52.0;
MS (EI) m/z (rel. intensity) 171 ([M]+, 60), 160 (70), 130
(55), 105 (60), 83 (100); HRMS (EI) m/z calcd. for
C11H9NO 171.0684, found 171.0676.
4.19. (E)-2-Allyl-3-(hex-1-enyl)isoindolin-1-one (34)
According to general protocol A, 1-hexyne (16)
(420 lL, 3.66 mmol), CH2Cl2 (10 mL), zirconocene hydro-
chloride (944 mg, 3.66 mmol), Me3Al (1.0 M in CH2Cl2,
3.66 mL, 3.66 mmol) and 31 (500 mg, 1.83 mmol) affor-
ded 341 mg (73%) of 34 as a colorless oil after purifica-
tion on SiO2 (EtOAc:hexanes, 3:7): IR (neat) 2957,
1208, 1141, 959, 751 cmÀ1 1H NMR d 7.67 (d, 1H,
;
J = 6.0 Hz), 7.49–7.32 (m, 3H), 6.89 (s, 1H), 5.79–5.58
(m, 1H), 4.91 (d, 1H, J = 17.1 Hz), 4.84 (d, 1H,
J = 10.5 Hz), 3.73–3.55 (m, 1H), 3.27–3.09 (m, 1H),
2.07–1.93 (m, 2H), 1.77–1.50 (m, 2H), 1.11 (s, 9H); 13C
NMR d 178.2, 167.4, 140.9, 137.1, 132.0, 131.8, 129.8,
123.2, 123.1, 114.9, 80.8, 39.5, 38.7, 30.7, 27.1, 26.6; MS
(EI) m/z (rel intensity) 301 ([M]+, 15), 246 (45), 216
(65), 200 (85), 146 (85), 133 (65); HRMS (EI) m/z calcd.
for C18H23NO3 301.1678, found 301.1681.
1
2926, 1697, 1468, 1396, 971, 748 cmÀ1; H NMR d 7.83
(d, 1H, J = 7.2 Hz), 7.57–7.38 (m, 2H), 7.33 (d, 1H,
J = 7.5 Hz), 5.97 (dt, 1H, J = 15.0, 6.9 Hz), 5.88–5.71
(m, 1H), 5.22–4.97 (m, 3H), 4.85 (d, 1H, J = 9.3 Hz),
4.59 (dd, 1H, J = 15.6, 4.5 Hz), 3.69 (dd, 1H, J = 15.3,
7.2 Hz), 2.12 (app q, 2H, J = 6.6 Hz), 1.48–1.28 (m,
4H), 0.91 (t, 3H, J = 6.9 Hz); 13C NMR d 167.7, 145.0,
138.2, 133.1, 131.7, 131.4, 128.2, 126.0, 123.4, 122.9,
117.4, 62.9, 42.5, 31.8, 31.1, 27.0, 22.0, 13.8; MS (EI)
m/z (rel intensity) 255 ([M]+, 30), 198 (100), 172 (55);
HRMS (EI) m/z calcd. for C17H21NO 255.1623, found
255.1627.
4.22. (E)-3-(Hex-1-enyl)-2-(pent-4-enyl)isoindolin-1-one
(37)
According to general protocol A, hexyne (16) (420 lL,
3.66 mmol), CH2Cl2 (10 mL), zirconocene hydrochloride
(944 mg, 3.66 mmol), Me3Al (1.0 M in CH2Cl2, 3.66 mL,
3.66 mmol) and 36 (552 mg, 1.83 mmol) afforded 368 mg
(72%) of 37 as a colorless oil after purification on SiO2
(EtOAc:hexanes, 3:7): IR (neat) 3076, 2967, 2928, 2860,
4.20. 2-(Pent-4-enyl)isoindoline-1,3-dione (35)
A solution of 4-penten-1-ol (3.51 mL, 34.0 mmol),
phthalimide 4 (5.00 mg, 34.0 mmol), and PPh3 (8.92 g,
34.0 mmol) in THF (220 mL) was cooled to 0 ꢁC and trea-
ted with DIAD (6.69 mL, 34.0 mmol) over 5 min. The reac-
tion mixture was warmed to r.t. and stirred for 6 h. The
solvent was evaporated, the residue was dissolved in
1693, 1468, 1404, 972, 749 cmÀ1 1H NMR d 7.72 (d,
;
1H, J = 7.5 Hz), 7.44–7.28 (m, 2H), 7.23 (d, 1H,
J = 7.2 Hz), 5.94 (dt, 1H, J = 14.4, 6.6 Hz), 5.80–5.63

4628
J.G. Pierce et al. / Journal of Organometallic Chemistry 692 (2007) 4618–4629
[7] Achinami K, Ashizawa N, Kobayasui F. Japanese Patent 03,133,955,
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Chem. Abstr. 115 (1991) 255977j.
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(m, 1H), 5.03–4.82 (m, 3H), 4.75 (d, 1H, J = 9.0 Hz),
3.83–3.65 (m, 1H), 3.23–3.07 (m, 1H), 2.13–1.93 (m,
4H), 1.75–1.51 (m, 2H), 1.42–1.19 (m, 4H), 0.83 (t, 3H,
J = 6.9 Hz); 13C NMR d 167.6, 144.6, 137.5, 137.3,
131.7, 131.0, 127.9, 126.2, 122.9, 122.6, 114.7, 63.2, 39.4,
31.5, 30.8, 30.7, 27.3, 26.9, 21.8, 13.5; MS (EI) m/z (rel.
intensity) 283 ([M]+, 20), 228 (70), 160 (100), 146 (50),
76 (50); HRMS (EI) m/z calcd. for C19H25NO 283.1936,
found 283.1934.
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L. Shen, R.P. Hsung, Org. Lett. 7 (2005) 775, and references cited
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4.23. (Z)-7,8,9,11a-Tetrahydro-5H-azepino[2,1-a]isoindol-
5-one (38)
To a solution of 37 (150 mg, 0.529 mmol) in toluene
(100 mL) was added Ti(OiPr)4 (157 lL, 0.529 mmol) and
Grubbs 2nd generation catalyst (22.5 mg, 0.0265 mmol)
and the red solution was stirred at r.t. for 12 h and con-
centrated. The residue was purified by chromatography
on SiO2 (acetone:CH2Cl2, 0.4:9.6) to yield 70.7 mg
(67%) of 38 as a colorless oil: IR (neat) 3024, 2926,
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1680, 1469, 1419, 1298, 938, 709 cmÀ1
;
1H NMR
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(b) M.-J. Tranchant, C. Moine, R. Ben Othman, T. Bousquet, M.
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(CD2Cl2) d 7.76 (dd, 1H, J = 6.9, 1.2 Hz), 7.58–7.51 (m,
1H), 7.46 (app t, 2H, 7.2 Hz), 6.13–6.02 (m, 1H), 6.02–
5.91 (m, 1H), 4.49 (dd, 1H, J = 11.4, 2.1 Hz), 4.26
(ddd, 1H, J = 13.5, 6.6, 3.0 Hz), 3.22 (ddd, 1H,
J = 12.6, 9.6, 2.7 Hz), 2.81 (app ddd, 1H, J = 15.9, 7.8,
2.4 Hz), 2.53–2.26 (m, 2H), 2.25–2.09 (m, 1H); 13C
NMR (CD2Cl2) d 167.5, 145.9, 133.0, 132.7, 131.6,
128.8, 128.5, 123.5, 122.4, 60.6, 41.6, 35.2, 28.2; MS
(EI) m/z (rel. intensity) 199 ([M]+, 45), 145 (100), 117
(40), 90 (35); HRMS (EI) m/z calcd. for C13H13NO
199.0997, found 199.0991.
(d) S.M. Allin, C.J. Northfield, M.I. Page, A.M.Z. Slawin, Tetrahe-
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This work has been supported by the National Institutes
of Health – NIGMS CMLD Program (GM067082) and
Merck Research Laboratories. J.G.P. thanks the ACS
Division of Organic Chemistry for a Graduate Fellowship
sponsored by Wyeth.
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