PhI(OAc)2-mediated iminobromination for synthesis of bromomethyl cyclic imines starting from alkenyl carbonitriles and Grignard reagents

Article abstract of DOI:10.1016/j.tet.2010.11.060

PhI(OAc)₂-mediated iminobromination was developed starting from alkenyl carbonitriles and Grignard reagents. The present transformation is carried out by a sequence of nucleophilic addition of Grignard reagents to alkenyl carbonitriles to form

Full text of DOI:10.1016/j.tet.2010.11.060

Tetrahedron 67 (2011) 590e596
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
PhI(OAc)2-mediated iminobromination for synthesis of bromomethyl cyclic
imines starting from alkenyl carbonitriles and Grignard reagents
*
Stephen Sanjaya, Shunsuke Chiba
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
PhI(OAc)2-mediated iminobromination was developed starting from alkenyl carbonitriles and Grignard
reagents. The present transformation is carried out by a sequence of nucleophilic addition of Grignard
reagents to alkenyl carbonitriles to form NeH imines and their iminohalogenation by subsequent
treatment with PhI(OAc)2.
Received 14 September 2010
Received in revised form 27 October 2010
Accepted 16 November 2010
Available online 20 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Iminobromination
Bromomethyl cyclic imines
Alkenyl carbonitriles
Grignard reagents
PhI(OAc)2
1. Introduction
Our attention was turned to utilize alkenyl carbonitriles with
Grignard reagents to develop a CeN bond forming process on the
Molecular transformations that allow the construction of func-
tionalized organic frameworks from simple and ubiquitous starting
materials through multi-formation of chemical bonds in one-pot
fashion is an ideal process in organic synthesis from the atom-1 and
step-economical2 point of views. Electrophilic halocyclization of al-
kenes has been utilized as one of the most convenient methods to
access molecular complexity, where halogenating reagents effect
cyclizationofalkenes bearingintramolecular nucleophilic parts, such
as carboxy, hydroxy, amino, and amido as well as carbonyl oxygen.3
We have been interested in use of ubiquitous carbonitriles as
a nitrogen source for synthesis of azaheterocycles. We recently dis-
closed the copper-catalyzed synthesis of phenanthridine derivatives
from biaryl-2-carbonitriles and Grignard reagents under an oxygen
atmosphere,4 in which putative iminyl copper species derived from
the NeH imine intermediate might undergo intramolecular CeN
bond formation on the aromatic CeH bond (Scheme 1).
C]C bond via the NeH imine intermediate. Herein, we wish to
report PhI(OAc)2-mediated iminobromination starting from alkenyl
carbonitriles and Grignard reagents, providing functionalized cyclic
imines, such as bromomethyl dihydropyrroles and dihy-
droisoquinolines with one-pot formation of CeC, CeN, and CeBr
bonds. The present transformation is carried out by a sequence of
nucleophilic addition of Grignard reagents (ReMgBr) to alkenyl
carbonitriles to form NeH imines and their iminobromination by
subsequent treatment with PhI(OAc)2, where the bromine atom of
the counter anion of the Grignard reagents was incorporated into
the final products without utilizing additional bromine sources,
such as elemental bromine, N-bromosuccinimide (NBS),5 N-bro-
moacetamide (NBA), bromodimethylsulfonium bromide.6,7
2. Results and discussion
First of all, 2,2,4-trimethylpent-4-enenitrile (1a) and p-tol-
ylmagnesium bromide (2a) were chosen, and their intermolecular
addition reaction to form the NeH imine and its cyclization was
investigated. Addition of p-tolylmagnesium bromide (2a) to car-
bonitrile 1a occurred smoothly in Et2O at 60 ꢀC (in sealed tube).
After protonation with MeOH,8 DMF (the reaction was diluted to
0.1 M) and Cu(OAc)2 (20 mol %) were subsequently added, and the
reaction mixture was stirred at 80 ꢀC under an oxygen atmosphere
(1 atm) (Table 1, entry 1). After 8 h, a hydroimination product, cyclic
imine 3, was isolated in 43% yield. In addition to the formation of 3,
Scheme 1.
* Corresponding author. Tel.: þ65 81 6513 8013; fax: þ65 81 6791 1961; e-mail
address: shunsuke@ntu.edu.sg (S. Chiba).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.060

S. Sanjaya, S. Chiba / Tetrahedron 67 (2011) 590e596
591
cyclic imine 4aa bearing a CeBr bond was isolated in 6% yield.
When 1.1 equiv of Cu(OAc)2 was utilized without oxygen (under
a N2 atmosphere), the yield of 4aa was increased to 40% (entry 2). It
was found that treatment with PhI(OAc)2 (1.5 equiv) provided
brominated cyclic imine 4aa exclusively in 88% yield at room
temperature (entry 3). Oxone9 also worked well providing a slightly
reactions of alkenyl Grignard reagents afforded the corresponding
dihydropyrroles 4ag in 55% yield (entry 7), whilst no desired
product was observed from alkyl Grignard reagents, such as 2i
probably due to the instability of the resulting NeH imine in-
termediate (entry 8).
10
lower yield (76%, entry 4), while the other oxidants, such as NaIO4
and NaClO2 did not form 4aa at all (entries 5 and 6).
Table 2
Scope of Grignard reagentsa
1) R–MgBr 2
(1.2 equiv)
Table 1
Optimization of reaction conditionsa
Et2O, 60 °C, 2 h
(sealed tube)
then, MeOH
Br
Me
Me
1) Tol–MgBr 2a
(1.2 equiv)
Et2O, 60 °C, 2 h
N
N
C
R
Me
Br
2) PhI(OAc)2 (1.5 equiv)
DMF, rt
Me
(sealed tube)
then, MeOH
Me Me
1a
Me
Me
Me Me
4
N
N
N
+
C
Tol
Tol
2) oxidants, DMF
conditions
Me Me
Me Me
4aa
Entry
ReMgBr 2
Dihydropyrroles 4 (yield/%)b
Me Me
1a
3
1
2
3
4
5
6
7c
2a: R¼4-MeeC6H4
2b: R¼4-MeOeC6H4
2c: R¼2-MeeC6H4
2d: R¼2,6-Me2eC6H3
2e: R¼4-CleC6H4
2f: R¼2-thienyl
4aa (88)
4ab (92)
4ac (78)
4ad (12)
4ae (70)
4af (61)
4ag (55)
Entry
Oxidants
Conditions
Yield (%)b
3
4aa
1
2
3
4
5
6
Cu(OAc)2 (20 mol %) under O2 (1 atm)
Cu(OAc)2 (1.1 equiv) under N2 (1 atm)
PhI(OAc)2 (1.5 equiv)
Oxone (1.5 equiv)
NaIO4 (1.5 equiv)
80 ꢀC, 8 h
80 ꢀC, 6 h
rt, 0.5 h
rt, 0.5 h
rt, 0.5 h
rt, 0.5 h
43
49
0
6
40
88
2g: R =
Ph
8d
2i: R¼PhCH2CH2
4ah (0)
0
0
0
73
a
0 (97)c
0 (73)c
Reactions were run by treatment of carbonitrile 1a (0.35e0.4 mmol) with
1.2 equiv of Grignard reagents 2 in Et2O (sealed tube) at 60 ꢀC followed by the
addition of MeOH (3 equiv), DMF (reaction diluted to 0.1 M) and PhI(OAc)2
(1.5 equiv) at room temperature.
NaClO2 (1.5 equiv)
Entry 3 was optimized (best) conditions represents in bold.
a
Reactions were carried out using 0.35e0.4 mmol of carbonitrile 1a.
Isolated yields.
Isolated yield of 2,2,4-trimethyl-1-p-tolylpent-4-en-1-one formed via hydroly-
b
Isolated yields.
b
c
c
Nitrile 1a was treated with 2 equiv of alkenyl Grignard reagent 2g at 80 ꢀC for
6.5 h.
sis of the NeH imine.
d
18 h were required to consume nitrile 1a with Grignard reagent 2i.
A proposed reaction course of formation of bromomethyl cyclic
imine 4aa was outlined in Scheme 2. Addition of Grignard reagent
2a to carbonitrile 1a followed by protonation with MeOH provides
the NeH imine and MeOMgBr that was oxidized by PhI(OAc)2 to
generate Brþ species. Formation of bromonium cation followed by
intramolecular nucleophilic attack of imine affords cyclic imine
4aa.11,12
The effects of substituents on the alkenyl carbonitriles 1 were
examined using p-tolylmagnesium bromide (2a) (Table 3). The re-
action of 4-phenyl substituted 1b provided dihydropyrrole 4ba in
good yield (entry 1). From 5-phenyl and 5,5-dimethyl derivatives 1c
and 1d, only 5-exo-cyclization was observed exclusively (entries 8
and 9). 2,2-Dimethyl-, 2,2-diallyl-, and 2,2-diphenyl-4-penteneni-
triles (1eeg) could be utilized to access 4,4-disubstituted dihy-
dropyrroles (entries 4e6). A 2-azaspiro[4.5]dec-1-ene structure
4ha was efficiently constructed from 1-allylcyclohexanecarboni-
trile (1h) (entry 7). The reaction of 4-pentenenirile (1i) also pro-
ceeded to give dihydropyrrole 4ia while 8% yield of a-brominated
compound was isolated as a side product (entry 8).
Table 3
Scope on the substituents of alkenyl carbonitriles 1a
Entry
1
Nitriles 1
Ph
N
Dihydropyrroles 4 (yield/%)b
Br
Ph
N
1b
4ba (76)
C
Tol
Me Me
Scheme 2.
Me Me
Ph
Ph
Br
N
By utilizing PhI(OAc)2 as the oxidant (entry 3 in Table 1), we
examined the generality of this method for synthesis of bromo-
methyl dihydropyrroles starting from 4-pentenenitrile derivatives
1. First, the scope of Grignard reagents 2 was examined using nitrile
1a (Table 2). Aryl Grignard reagents bearing both electron-donating
and -withdrawing groups on the benzene ring as well as 2-thie-
nylmagnesium bromide provided the desired dihydropyrroles 4 in
good yields except for the reaction with the sterically hindered 2,6-
dimethylphenylmagnesium bromide 2d (entries 1e6). The
2
3
N
4ca (87)
1c
C
c
Tol
(dr = 76:11)
Me Me
Me Me
Me
Me
Me
Br
N
4da (65)
Me
N
1d
Tol
C
Me Me
(continued on next page)
Me Me

592
S. Sanjaya, S. Chiba / Tetrahedron 67 (2011) 590e596
Table 3 (continued )
3. Conclusion
Entry
Nitriles 1
Dihydropyrroles 4 (yield/%)b
Br
In conclusion, a synthetic method for the preparation of bro-
momethyl cyclic imines has been developed starting from a variety
of alkenyl carbonitriles and Grignard reagents via PhI(OAc)2-me-
diated iminobromination. Continuous studies on the scope and
synthetic applications of the present method toward various het-
erocycles are in progress.
N
N
C
4
5
4ea (75)
4fa (71)
4ga (57)
4ha (83)
1e
Tol
Me Me
Me Me
Br
N
N
C
1f
Tol
4. Experimental section
4.1. General
Br
N
N
C
6
7
1g
Tol
Tol
1H NMR (400 MHz) spectra were recorded on a Bruker Avance
400 spectrometer in CDCl3 [using tetramethylsilane (for 1H,
Ph Ph
Ph Ph
Br
d
¼0.00) as internal standard]. 13C NMR (100 MHz) spectra on
N
N
a Bruker Avance 400 spectrometer in CDCl3 [using CHCl3 (for 13C,
C
1h
d
¼77.0) as internal standard]. The following abbreviations were
used to explain the multiplicities: s¼singlet, d¼doublet, t¼triplet,
m¼multiplet, br¼broad. IR spectra were recorded on a Shimadzu IR
Prestige-21 FTIR Spectrometer. High-resolution mass spectra were
obtained with a Finnigan MAT 95 XP mass spectrometer (Thermo
Electron Corporation). Melting points were uncorrected and were
recorded on a Buchi B-54 melting point apparatus.
Br
N
8
N
1i
4ia (64)d
C
Tol
a
Reactions were run by treatment of carbonitrile 1a (0.35e0.4 mmol) with
1.2 equiv of Grignard reagents 2 in Et2O (sealed tube) at 60 ꢀC followed by the
addition of MeOH (3 equiv), DMF (reaction diluted to 0.1 M) and PhI(OAc)2
(1.5 equiv) at room temperature.
Flash column chromatography was performed using Merck sil-
ica gel 60 with distilled hexane and ethyl acetate. Diisopropylamine
was purchased from Alfa Aesar, distilled from KOH and stored over
KOH. Tetrahydrofuran (THF), acetonitrile, and diethyl ether (Et2O)
were taken from a solvent purification system (PS-400-5, In-
novative Technology, Inc.). Methanol (MeOH) was distilled from
sodium and stored over MS 3A. N,N,-Dimethylformamide (DMF)
was purchased from SigmaeAldrich, Pte. Ltd. Acetone (HPLC grade)
was purchased from Tedia Company, Inc.
b
Isolated yields.
c
The ratio was determined by weight after separation of two isomers by column
chromatography. The relative stereochemistry was not determined.
d
a
-Brominated product 4ia-Br was isolated in 8% yield.
Having a protocol to prepare bromomethyl dihydropyrroles 4,
we envisioned the construction of six-membered azaheterocycles
(Scheme 3). The reaction of 2,2-dimethylhex-5-enenitrile (5) with
p-tolylmagnesium bromide (2a) afforded the desired bromomethyl
tetrahydropyridine 613 in only 14% yield along with acyclic bromi-
nated NeH imine 714 in 13% yield. On the contrary, it was found that
the reactions of 2-allylbenzonitrile (8) with aryl Grignard reagents
All liquid starting materials were Kugelrohr distilled before use.
4-Pentenenitrile (1i) was purchased from SigmaeAldrich, Pte. Ltd.,
and was distilled with Kugelrohr before use (27 mm Hg/50 ꢀC). All
solid products were recrystallized from hexane and ethyl acetate.
4.2. Synthesis of alkenyl carbonitriles
could
provide
3-bromomethyl-3,4-dihydroisoquinolines
9
4.2.1. Synthesis of 1aee, 1geh, and 5:15 a typical procedure for
synthesis of 1d16. To a 100 mL round-bottom flask was added dii-
sopropylamine (2.2 mL, 15.4 mmol) and n-BuLi (9.2 mL, 14.7 mmol)
in THF (18 mL), and the reaction mixture was stirred at 0 ꢀC for
30 min. The mixture was then cooled down to ꢁ78 ꢀC and iso-
butyronitrile (1.3 mL, 14.0 mmol) was slowly added. After stirring
for 1 h,1-bromo-3-methylbut-2-ene (1.8 mL,15.4 mmol) was added
dropwise and the reaction mixture was allowed to warm up to
room temperature while stirring overnight. The reaction was
quenched with saturated aqueous NH4Cl solution. Organic mate-
rials were then extracted three times with 50 mL of Et2O. The or-
ganic phase was washed with water and brine, and dried over
MgSO4. After filtration, the solvent was evaporated to give a crude
mixture, which was purified by Kugelrohr distillation to provide
2,2,5-trimethylhex-4-enenitrile (1d) (1.52 g, 11.1 mmol) for 79%
yield (5 mm Hg/86e88 ꢀC).
smoothly in good to moderate yields.
Colorless oil; 1H NMR (400 MHz, CDCl3)
s), 1.77 (3H, s), 2.23 (2H, d, J¼7.6 Hz), 5.25 (1H, ddt, J¼1.3, 1.3,
d 1.32 (6H, s), 1.65 (3H,
7.6 Hz); 13C NMR (100 MHz, CDCl3)
d 18.1, 25.9, 26.2, 32.8, 39.1,
118.2, 125.3, 136.4; distillation: 5 mm Hg/86e88 ꢀC.
4.2.1.1. 2,2,4-Trimethylpent-4-enenitrile (1a)17. Yield 90%; Col-
orless oil; 1H NMR (400 MHz, CDCl3)
d
1.36 (6H, s), 1.90 (3H, s), 2.26
(2H, s), 4.84 (1H, s), 4.98 (1H, s); 13C NMR (100 MHz, CDCl3)
23.6,
27.0, 31.3, 48.5, 116.1, 125.4, 140.6; distillation: 26 mm Hg/70e72 ꢀC.
d
Scheme 3.

S. Sanjaya, S. Chiba / Tetrahedron 67 (2011) 590e596
593
4.2.1.2. 2,2-Dimethyl-4-phenylpent-4-enenitrile
24%; Colorless oil; 1H NMR (400 MHz, CDCl3)
1.28 (6H, s), 2.80 (2H,
s), 5.32 (1H, s), 5.47 (1H, s), 7.28e7.43 (5H, m); 13C NMR (100 MHz,
(1b)18. Yield
aqueous NH4Cl solution at room temperature. Organic materials
were then extracted three times with 100 mL of Et2O. The organic
phase was washed with water and brine, and dried over MgSO4.
After filtration, the solvent was evaporated to give a crude mixture,
which was purified by Kugelrohr distillation, affording product 1f
(3.41 g, 21.1 mmol) for 81% yield.
d
CDCl3) d 27.1, 33.1, 45.5, 118.5, 124.6, 126.5, 127.8, 128.5, 141.6, 144.0;
distillation: 0.9 mm Hg/105e110 ꢀC.
4.2.1.3. (E)-2,2-Dimethyl-5-phenylpent-4-enenitrile (1c)19. Yield
Colorless oil; 1H NMR (400 MHz, CDCl3)
d
2.27 (6H, d, J¼7.3 Hz),
91%; White solid; 1H NMR (400 MHz, CDCl3)
d
1.39 (6H, s), 2.44 (2H,
5.20 (3H, d, J¼17.0 Hz), 5.25 (3H, d, J¼10.2 Hz), 5.85 (ddd, J¼7.3,
dd, J¼1.2, 7.5 Hz), 6.26 (1H, td, J¼7.5, 15.7 Hz), 6.51 (1H, d,
10.2, 17.0 Hz); 13C NMR (100 MHz, CDCl3)
d 40.0, 40.2, 120.3, 122.6,
J¼15.7 Hz), 7.23e7.25 (1H, m), 7.30e7.34 (2H, m), 7.38e7.40 (2H,
131.6; distillation: 5 mm Hg/90e95 ꢀC.
m); 13C NMR (100 MHz, CDCl3)
d 26.3, 32.6, 44.3, 123.5, 124.8, 126.3,
127.7, 128.6, 134.8, 136.7; recrystallized from hexane and ethyl
acetate.
4.2.3. Synthesis of 2-allylbenzonitrile (8)21,22. To a 100 mL round-
bottomed flask was added n-BuMgBr (10 mL,1.2 M in THF,12 mmol)
and n-BuLi (15 mL, 1.6 M in hexane, 24 mmol) at 0 ꢀC in THF
(20 mL), and stirred for 10e15 min. The mixture was then cooled
down to ꢁ78 ꢀC and 2-bromobenzonitrile (1.82 g, 10 mmol) in THF
(20 mL) was added dropwise. It was then allowed to stir at ꢁ78 ꢀC
for 1 h. Meanwhile, CuCN (269.6 mg, 3.01 mmol) and LiCl
(254.3 mg, 6.00 mmol) in THF (3 mL) were added to a 15 mL round-
bottomed flask and stirred at room temperature until all solids
were dissolved and the mixture turned to blue color. The resulting
CuCNꢂ2LiCl solution and allyl bromide (3.5 mL, 40 mmol) were
then added onto the reaction mixture at ꢁ78 ꢀC, respectively. After
1 h stirring, the reaction mixture was then quenched with saturated
aqueous NH4Cl at room temperature. Organic materials were then
extracted three times with 50 mL of Et2O. The organic phase was
washed with water and brine, and dried over MgSO4. After filtra-
tion, the solvent was evaporated to give crude mixture, which was
purified by Kugelrohr distillation to provide 1f (0.93 g, 6.49 mmol)
for 65% yield.
4.2.1.4. 2,2-Dimethylpent-4-enenitrile (1e)15. Yield 60%; Color-
less oil; 1H NMR (400 MHz, CDCl3)
d 1.34 (6H, s), 2.28 (2H, d,
J¼7.3 Hz), 5.16e5.24 (2H, m), 5.82e5.92 (1H, m); 13C NMR
(100 MHz, CDCl3)
d 26.2, 32.1, 45.0, 119.9, 124.7, 132.2; distillation:
26 mm Hg/70e75 ꢀC.
4.2.1.5. 2,2-Diphenylpent-4-enenitrile (1g)15. Yield 82%; Color-
less oil; 1H NMR (400 MHz, CDCl3)
d
3.14 (2H, d, J¼7.0 Hz),
5.16e5.23 (2H, m), 5.66e5.76 (1H, m), 7.27e7.40 (10H, m); 13C NMR
(100 MHz, CDCl3)
d 43.9, 51.7, 120.4, 121.9, 127.0, 127.9, 128.8, 131.8,
139.7; distillation: 1.6 mm Hg/147e148 ꢀC.
4.2.1.6. 1-Allylcyclohexanecarbonitrile (1h)15. Yield 87%; Color-
less oil; 1H NMR (400 MHz, CDCl3)
d 1.12e1.28 (3H, m), 1.56e1.64
(2H, m), 1.66e1.75 (3H, m), 1.96 (2H, d, J¼12.9 Hz), 2.28 (2H, d,
J¼7.4 Hz), 5.15e5.22 (2H, m), 5.84e5.94 (1H, m); 13C NMR
(100 MHz, CDCl3)
d
23.0, 25.3, 35.3, 38.8, 44.6, 119.6, 123.3, 131.9;
Colorless oil; 1H NMR (400 MHz, CDCl3)
d
3.62 (2H, d, J¼6.6 Hz),
distillation: 5 mm Hg/95e100 ꢀC.
5.12 (1H, dd, J¼1.4, 16.8 Hz), 5.16 (1H, dd, J¼1.4, 8.6 Hz), 5.91e5.99
(1H, m), 7.28 (1H, d, J¼7.7 Hz), 7.33 (1H, dd, J¼7.7, 7.7 Hz), 7.53 (1H,
dd, J¼7.7, 7.7 Hz), 7.63 (1H, d, J¼7.7 Hz); 13C NMR (100 MHz, CDCl3)
4.2.1.7. 2,2-Dimethylhex-5-enenitrile (5)19. Yield 75%; Colorless
oil; 1H NMR (400 MHz, CDCl3)
d
1.36 (6H, s), 1.60e1.64 (2H, m),
d 38.5, 112.5, 117.4, 117.9, 126.8, 129.7, 132.8 (2C overlapped), 134.9,
2.22e2.28 (2H, m), 5.01 (1H, d, J¼10.2 Hz), 5.08 (1H, d, J¼17.1 Hz),
143.8; distillation: (4 mm Hg/93e95 ꢀC).
5.77e5.87 (1H, m); 13C NMR (100 MHz, CDCl3)
d 26.7, 29.5, 32.2,
40.2, 115.5, 124.9, 137.0; distillation: 26 mm Hg/90e95 ꢀC.
4.3. Synthesis of bromomethyl cyclic imines: a typical
procedure for synthesis of 4aa (Table 1, entry 3)
4.2.2. Synthesis of 2,2-diallylpent-4-enenitrile (1f)20. To a 200 mL
round-bottom flask was added diisopropylamine (11.3 mL,
80.6 mmol) and n-BuLi (50 mL, 80 mmol) in THF (120 mL) and the
reaction mixture was stirred at 0 ꢀC. The lithium diisopropylamide
(LDA) formed was used in three portions. Meanwhile, to a 300 mL
round-bottomed flask was added acetonitrile (1.4 mL, 26 mmol) in
THF (15 mL) and cooled down to ꢁ78 ꢀC. After the first 1/3 portion
of LDA was added dropwise, the mixture was stirred for 15 min.
Allyl bromide (2.4 mL, 27.3 mmol) was then added dropwise and
stirred for 30 min and allowed to warm up to room temperature.
The reaction mixture was again cooled down to ꢁ78 ꢀC for second
addition. Second 1/3 portion of LDA was added and the mixture was
stirred for 15 min. Allyl bromide (2.4 mL, 27.3 mmol) was then
added dropwise and stirred for 30 min and allowed to warm up to
room temperature. The reaction mixture was again cooled down to
ꢁ78 ꢀC for third addition. The last 1/3 portion of LDA was added and
stirred for 15 min. Allyl bromide (2.4 mL, 27.3 mmol) was then
added dropwise and the mixture was stirred overnight while
warming up to room temperature.
To a 10 mL Schlenk tube was added nitrile 1a (41.6 mg,
0.338 mmol) in Et2O (1.0 mL) and p-tolylmagnesium bromide
(0.40 mL, 0.354 mmol, 0.89 M in Et2O) was added slowly. The re-
action was then heated at 60 ꢀC for 1 h. After no starting material
spot was observed on TLC, the mixture was quenched with distilled
MeOH (60
m
L) at 0 ꢀC. DMF (4 mL) and PhI(OAc)2 (165.0 mg,
0.512 mmol) was then added immediately. The mixture was further
stirred at rt for 30 min. The mixture was then poured into 20 mL of
saturated aqueous NH4Cl upon completion and extracted three
times with 30 mL of Et2O. The organic phase was then washed with
water, brine, and finally dried over MgSO4. The organic extract was
filtered and the solvent was evaporated to give crude mixture,
which was purified by flash column chromatography (hexane/ethyl
acetate¼95:5) to provide product 4aa (87.6 mg, 0.298 mmol) for
88% yield.
Rf¼0.31 (hexane/ethyl acetate¼9:1); yellow oil; FTIR (NaCl)
3028, 2965, 2930, 1605, 1564, 1466, 1450, 664 cmꢁ1 1H NMR
;
(400 MHz, CDCl3) d 1.36 (3H, s), 1.45 (3H, s), 1.49 (3H, s), 1.82 (1H, d,
The reaction may not have completed as two spots were ob-
served on TLC after being stained with KMnO4. A fourth 1/3
equivalent of LDA mixture was prepared as stated above [diiso-
propylamine (4.0 mL, 28.6 mmol) and n-BuLi (17.1 mL, 27.3 mmol,
1.6 M in hexane) in THF (25 mL)] and added to the reaction mixture
at ꢁ78 ꢀC. Allyl bromide (2.4 mL, 27.3 mmol) was then added
dropwise and stirred for 1 h and allowed to warm up to room
temperature. The reaction mixture was quenched with saturated
J¼13.3 Hz), 2.21 (1H, d, J¼13.3 Hz), 2.37 (3H, s), 3.57 (2H, s), 7.18 (2H,
d, J¼8.1 Hz), 7.61 (2H, d, J¼8.1 Hz); 13C NMR (100 MHz, CDCl3)
d 21.3,
27.5, 28.0, 29.3, 44.7, 50.5, 51.8, 71.9, 128.1, 128.9, 131.7, 139.7;
ESIMS: found: m/z 294.0864. Calcd for C15H2179BrN: (MþH)þ
294.0857.
4.3.1. 2,2,4,4-Tetramethyl-5-p-tolyl-3,4-dihydro-2H-pyrrole (3) (Table
1, entries
1
and 2). Rf¼0.35 (hexane/ethyl acetate¼9:1); 49%

594
S. Sanjaya, S. Chiba / Tetrahedron 67 (2011) 590e596
(38.5 mg); yellow oil; FTIR (NaCl) 3010, 2967, 2934, 1605, 1564,
1468, 1452 cmꢁ1; 1H NMR (400 MHz, CDCl3)
1.35 (6H, s), 1.37 (6H,
44.4, 50.3, 51.9, 72.1, 128.5, 129.5, 133.0, 135.7, 178.1; ESIMS: found:
d
m/z 314.0307. Calcd for C14H1879Br35ClN: (MþH)þ 314.0311.
s), 1.87 (2H, s), 2.36 (3H, s), 7.16 (2H, d, J¼8.2 Hz), 7.59 (2H, d,
J¼8.2 Hz); 13C NMR (100 MHz, CDCl3)
d
21.3, 28.9, 30.8, 51.6, 54.5,
4.3.8. 2-(Bromomethyl)-2,4,4-trimethyl-5-(thiophen-2-yl)-3,4-dihy-
dro-2H-pyrrole (4af). Rf¼0.50 (hexane/ethyl acetate¼9:1); 61%
(62.3 mg); colorless oil; FTIR (NaCl) 3019, 2967, 2930, 1593, 1466,
68.7, 128.0, 128.7, 132.2, 139.1, 176.1; ESIMS: found: m/z 216.1743.
Calcd for C15H22N: (MþH)þ 216.1752.
1450, 1431, 665 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.47 (3H, s), 1.49
4.3.2. 2,2,4-Trimethyl-1-p-tolylpent-4-en-1-one (Table 1, entries 5
and 6). Rf¼0.70 (hexane/ethyl acetate¼9:1); 97% (78.0 mg); yellow
oil; FTIR (NaCl) 3019, 2968, 2926, 1670, 1607, 1570, 1468,
(3H, s), 1.50 (3H, s), 1.83 (1H, d, J¼13.4 Hz), 2.22 (1H, d, J¼13.4 Hz),
3.54 (2H, dd, J¼10.0, 17.8 Hz), 7.06 (1H, dd, J¼3.6, 5.0 Hz), 7.38 (1H,
d, J¼5.0 Hz), 7.49 (1H, d, J¼3.6 Hz); 13C NMR (100 MHz, CDCl3)
1449 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
1.33 (6H, s), 1.62 (3H, s),
d 27.7, 28.3, 29.2, 44.3, 50.8, 51.5, 72.6, 127.4, 128.2, 128.7, 137.7,
2.37 (3H, s), 2.58 (2H, s), 4.64 (1H, d, J¼1.2 Hz), 4.80 (1H, d,
172.6; ESIMS: found: m/z 286.0269. Calcd for C12H1779BrNS:
(MþH)þ 286.0265.
J¼1.2 Hz), 7.19 (2H, d, J¼8.1 Hz), 7.66 (2H, d, J¼8.1 Hz); 13C NMR
(100 MHz, CDCl3)
d 21.3, 24.2, 26.8, 47.4, 48.5, 114.4, 128.3, 128.6,
135.8, 141.4, 142.4, 207.9; ESIMS: found: m/z 217.1596. Calcd for
4.3.9. (E)-2-(Bromomethyl)-2,4,4-trimethyl-5-styryl-3,4-dihydro-
2H-pyrrole (4ag). Rf¼0.40 (hexane/acetone¼85:15); 55% (65.7 mg,
purified with hexane/acetone¼9:1); colorless oil; FTIR (NaCl) 3019,
C15H21O: (MþH)þ 217.1592.
4.3.3. 2-(Chloromethyl)-2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-
pyrrole (4aa-Cl) (Ref. 12; the product from 1a and PhMgCl). Rf¼0.31
(hexane/ethyl acetate¼9:1); 41% (34.0 mg); colorless oil; FTIR
(NaCl) 3017, 2997, 1665, 1572, 1495, 1468, 1445, 698 cmꢁ1; 1H NMR
2961, 2932, 1639, 1589, 1495, 1449, 696 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
d
1.32 (3H, s), 1.33 (3H, s), 1.46 (3H, s), 1.75 (1H, d, J¼13.4 Hz),
2.12 (1H, d, J¼13.4 Hz), 3.53 (2H, dd, J¼10.0, 17.5 Hz), 6.68 (1H, d,
J¼16.3 Hz), 7.31e7.38 (3H, m), 7.49e7.53 (3H, m); 13C NMR
(400 MHz, CDCl3)
d
1.35 (3H, s), 1.44 (3H, s), 1.45 (3H, s), 1.80 (1H, d,
(100 MHz, CDCl3) d 27.5, 27.8, 28.5, 44.4, 49.1, 50.7, 72.7, 119.5, 127.3,
J¼13.3 Hz), 2.22 (1H, d, J¼13.3 Hz), 3.65 (2H, dd, J¼10.7, 13.7 Hz),
128.7, 129.0, 136.0, 137.7, 177.3; ESIMS: found: m/z 306.0855. Calcd
7.34e7.42 (3H, m), 7.65e7.68 (2H, m); 13C NMR (100 MHz, CDCl3)
for C16H2179BrN: (MþH)þ 306.0857.
d
26.9, 27.9, 29.2, 49.4, 52.0, 54.0, 72.7, 128.0, 128.2, 129.5, 134.7,
179.5; ESIMS: found: m/z 236.1201. Calcd for C14H19ClN: (MþH)þ
4.3.10. 2-(Bromomethyl)-4,4-dimethyl-2-phenyl-5-p-tolyl-3,4-dihy-
dro-2H-pyrrole (4ba). Rf¼0.63 (hexane/ethyl acetate¼9:1); 76%
(93.3 mg); white solid; mp 85e87 ꢀC; FTIR (NaCl) 3019, 2965, 2930,
236.1206.
4.3.4. 2-(Bromomethyl)-5-(4-methoxyphenyl)-2,4,4-trimethyl-3,4-
dihydro-2H-pyrrole (4ab). Rf¼0.40 (hexane/ethyl acetate¼9:1); 92%
(107.4 mg); white solid; mp 65e67 ꢀC; FTIR (NaCl) 3017, 2965, 2936,
1609, 1568, 1464, 1443, 1169, 667 cmꢁ1; 1H NMR (400 MHz, CDCl3)
1634, 1522, 1476, 1423, 669 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.12
(3H, s), 1.41 (3H, s), 2.34 (1H, d, J¼13.0 Hz), 2.39 (3H, s), 2.59 (1H, d,
J¼13.0 Hz), 3.75 (1H, d, J¼10.2 Hz), 3.90 (1H, d, J¼10.2 Hz), 7.22 (2H,
d, J¼8.1 Hz), 7.25e7.27 (1H, m), 7.31e7.35 (2H, m), 7.49 (2H, d,
d
1.38 (3H, s),1.47 (3H, s),1.48 (3H, s),1.82 (1H, d, J¼13.3 Hz), 2.20 (1H,
J¼7.4 Hz), 7.71 (2H, d, J¼8.1 Hz); 13C NMR (100 MHz, CDCl3)
d 21.4,
d, J¼13.3 Hz), 3.56 (2H, s), 3.83(3H, s), 6.89(2H, d, J¼8.7 Hz), 7.71 (2H,
26.9, 27.7, 45.3, 50.7, 51.7, 76.2, 126.2, 127.1, 128.2, 128.3, 128.9, 131.7,
139.8, 145.6, 179.8; ESIMS: found: m/z 356.1013. Calcd for
C20H2379BrN: (MþH)þ 356.1014.
d, J¼8.7 Hz); 13C NMR (100 MHz, CDCl3)
d 27.5, 28.1, 29.4, 44.8, 50.8,
51.6, 55.3, 71.6, 113.6, 126.9, 129.8, 160.8, 178.2; ESIMS: found: m/z
310.0811. Calcd for C15H2179BrNO: (MþH)þ 310.0807.
4.3.11. 2-(Bromo(phenyl)methyl)-4,4-dimethyl-5-p-tolyl-3,4-dihy-
dro-2H-pyrrole (4ca-major). Rf¼0.48 (hexane/ethyl acetate¼9:1);
76% (95.7 mg); colorless oil; FTIR (NaCl) 3028, 2959, 2926, 1601,
4.3.5. 2-(Bromomethyl)-2,4,4-trimethyl-5-o-tolyl-3,4-dihydro-2H-
pyrrole (4ac). Rf¼0.30 (hexane/ethyl acetate¼9:1); 78% (85.9 mg);
pale yellow solid; mp 53e55 ꢀC; FTIR (NaCl) 3010, 2965, 2940,
1632, 1601, 1491, 1468, 1450, 665 cmꢁ1; 1H NMR (400 MHz, CDCl3)
1562, 1495, 1452, 698 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.24 (3H,
s), 1.36 (3H, s), 1.60 (1H, dd, J¼9.3, 12.8 Hz), 1.88 (1H, dd, J¼6.9,
12.8 Hz), 2.37 (3H, s), 4.64 (1H, ddd, J¼6.9, 7.3, 9.3 Hz), 4.97 (1H, d,
J¼7.3 Hz), 7.19 (2H, d, J¼8.1 Hz), 7.27e7.31 (1H, m), 7.33e7.38 (2H,
m), 7.55e7.57 (2H, m), 7.67 (2H, d, J¼8.1 Hz); 13C NMR (100 MHz,
d
1.24 (3H, s), 1.27 (3H, s), 1.52 (3H, s), 1.83 (1H, d, J¼13.4 Hz), 2.24
(1H, d, J¼13.4 Hz), 2.35 (3H, s), 3.60 (2H, dd, J¼10.0, 19.4 Hz),
7.12e7.25 (4H, m); 13C NMR (100 MHz, CDCl3)
20.1, 27.3, 27.8,
d
28.4, 44.2, 48.0, 54.0, 73.4, 124.8, 127.6, 128.2, 130.5, 134.7, 136.2,
180.0; ESIMS: found: m/z 294.0858. Calcd for C15H2179BrN:
(MþH)þ 294.0857.
CDCl3) d 21.4, 26.3, 26.8, 46.4, 50.7, 58.7, 73.5, 128.1, 128.3, 128.5,
128.9, 131.4, 139.9, 140.0, 180.6; ESIMS: found: m/z 356.1018. Calcd
for C20H2379BrN: (MþH)þ 356.1014.
4.3.6. 2-(Bromomethyl)-5-(2,6-dimethylphenyl)-2,4,4-trimethyl-3,4-
dihydro-2H-pyrrole (4ad). Rf¼0.31 (hexane/ethyl acetate¼9:1); 12%
(13.1 mg); colorless oil; FTIR (NaCl) 3019, 2965, 2932, 1632, 1599,
4.3.12. 2-(Bromo(phenyl)methyl)-4,4-dimethyl-5-p-tolyl-3,4-dihy-
dro-2H-pyrrole (4ca-minor). Rf¼0.38 (hexane/ethyl acetate¼9:1);
11% (14.7 mg); colorless oil; FTIR (NaCl) 3028, 2959, 2926, 1601,
1468, 1447, 667 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.35 (3H, s), 1.44
1562, 1495, 1452, 698 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.35 (3H,
(3H, s), 1.49 (3H, s), 1.82 (1H, d, J¼13.3 Hz), 2.20 (1H, d, J¼13.3 Hz),
s), 1.39 (3H, s), 2.09 (2H, dd, J¼2.1, 8.5 Hz), 2.36 (3H, s), 4.52 (1H,
ddd, J¼5.4, 7.8, 7.8 Hz), 5.49 (1H, d, J¼5.4 Hz), 7.18 (2H, d, J¼7.9 Hz),
7.26e7.37 (3H, m), 7.49 (2H, dd, J¼1.2, 8.2 Hz), 7.63 (2H, d,
2.33 (6H, s), 3.57 (2H, s), 7.03 (1H, br s), 7.26 (2H, br s); 13C NMR
(100 MHz, CDCl3) d 21.3, 27.4, 27.9, 29.3, 44.6, 50.2, 52.0, 71.9, 125.8,
131.2, 134.6, 137.7, 179.8; ESIMS: found: m/z 308.1012. Calcd for
J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d 21.4, 26.7, 45.4, 50.5, 60.6,
C16H2379BrN: (MþH)þ 308.1014.
73.1, 128.1, 128.2, 128.3, 128.5, 128.9 (2C, overlapped), 131.2, 140.1,
180.9; ESIMS: found: m/z 356.1018. Calcd for C20H2379BrN: (MþH)þ
356.1014.
4.3.7. 2-(Bromomethyl)-5-(4-chlorophenyl)-2,4,4-trimethyl-3,4-di-
hydro-2H-pyrrole (4ae). Rf¼0.38 (hexane/ethyl acetate¼9:1); 70%
(82.2 mg); white solid; mp 63e66 ꢀC; FTIR (NaCl) 3019, 2965, 2930,
4.3.13. 2-(2-Bromopropan-2-yl)-4,4-dimethyl-5-p-tolyl-3,4-dihydro-
2H-pyrrole (4da). Rf¼0.63 (hexane/ethyl acetate¼9:1); 65%
(73.4 mg); white solid; mp 105e107 ꢀC; FTIR (NaCl) 3019, 2968,
2928, 1634, 1605, 1562, 1464, 669 cmꢁ1; 1H NMR (400 MHz, CDCl3)
1638, 1522, 1476, 1423, 669 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.35
(3H, s), 1.44 (3H, s), 1.49 (3H, s), 1.83 (1H, d, J¼13.3 Hz), 2.21 (1H, d,
J¼13.3 Hz), 3.57 (2H, dd, J¼10.0 Hz, 19.1 Hz), 7.35 (2H, d, J¼8.5 Hz),
7.64 (2H, d, J¼8.5 Hz); 13C NMR (100 MHz, CDCl3)
d
27.4, 27.8, 29.2,
d 1.36 (3H, s), 1.44 (3H, s), 1.89 (3H, s), 1.93e1.99 (3H, s, 1H,

S. Sanjaya, S. Chiba / Tetrahedron 67 (2011) 590e596
595
overlapped), 2.08 (1H, dd, J¼6.9, 12.6 Hz), 2.39 (3H, s), 4.03 (1H, dd,
J¼6.9, 9.3 Hz), 7.20 (1H, d, J¼8.1 Hz), 7.66 (2H, d, J¼8.1 Hz); 13C NMR
10.3 Hz), 3.87 (1H, dd, J¼4.1, 10.3 Hz), 4.59e4.65 (1H, m), 5.29 (1H,
d, J¼7.0 Hz), 7.25 (2H, d, J¼8.2 Hz), 7.83 (2H, d, J¼8.2 Hz); 13C NMR
(100 MHz, CDCl3)
d
21.3, 26.6, 26.7, 31.0, 32.3, 45.3, 50.5, 70.8, 77.9,
(100 MHz, CDCl3) d 21.5, 36.0, 41.0, 48.2, 70.8, 128.3, 128.4, 129.4,
128.0, 128.9, 131.8, 139.7, 180.3; ESIMS: found: m/z 308.1024. Calcd
141.9, 171.9; ESIMS: found: m/z 329.9492. Calcd for C12H1479Br2N:
(MþH)þ 329.9493.
for C16H2379BrN: (MþH)þ 308.1014.
4.3.14. 2-(Bromomethyl)-4,4-dimethyl-5-p-tolyl-3,4-dihydro-2H-
pyrrole (4ea). Rf¼0.20 (hexane/ethyl acetate¼9:1); 75% (80.1 mg);
yellow oil; FTIR (NaCl) 3030, 2959, 2928, 1599, 1560, 1464, 1452,
4.3.20. 2-(Bromomethyl)-5,5-dimethyl-6-p-tolyl-2,3,4,5-tetrahy-
dropyridine (6). Rf¼0.10 (hexane/ethyl acetate¼9:1); 14% (14.7 mg);
colorless oil (very unstable and decomposed to a complex mixture
at room temperature); FTIR (NaCl) 3010, 2959, 2928, 1632, 1510,
665 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.38 (3H, s), 1.39 (3H, s), 1.78
(1H, dd, J¼8.7, 12.7 Hz), 2.14 (1H, dd, J¼6.9, 12.7 Hz), 2.37 (3H, s),
3.59 (1H, dd, J¼7.4, 9.8 Hz), 3.79 (1H, dd, J¼4.2, 9.8 Hz), 4.31e4.36
(1H, m), 7.18 (2H, d, J¼8.0 Hz), 7.62 (2H, d, J¼8.0 Hz); 13C NMR
1456, 665 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.12 (3H, s), 1.19 (3H,
s), 1.69 (1H, dd, J¼4.3, 9.7 Hz), 1.73e1.85 (1H, m), 1.90e1.94 (1H, m),
2.34 (3H, s), 3.65 (1H, dd, J¼6.6, 9.7 Hz), 3.75 (1H, dd, J¼3.2, 9.7 Hz),
3.78e3.82 (1H, m), 7.13 (2H, d, J¼7.9 Hz), 7.18 (2H, d, J¼7.9 Hz); 13C
(100 MHz, CDCl3)
d 21.4, 26.4, 27.0, 38.0, 46.6, 50.9, 68.2, 127.9,
128.9, 131.4, 139.9, 181.1; ESIMS: found: m/z 280.0712. Calcd for
NMR (100 MHz, CDCl3) d 21.2, 23.4, 27.2, 28.3, 35.6, 35.7, 39.8, 58.8,
C14H1979BrN: (MþH)þ 280.0701.
127.5, 128.4, 137.4, 138.1, 178.0; ESIMS: found: m/z 294.0851. Calcd
for C15H2179BrN: (MþH)þ 294.0857.
4.3.15. 4,4-Diallyl-2-(bromomethyl)-5-p-tolyl-3,4-dihydro-2H-pyr-
role (4fa). Rf¼0.21 (hexane/ethyl acetate¼9:1); 71% (83.4 mg);
yellow oil; FTIR (NaCl) 3030, 2959, 2920, 1638, 1601, 1562, 1447,
4.3.21. 4-Bromo-2,2-dimethyl-1-p-tolylhex-5-en-1-imine
(7). Rf¼0.42 (hexane/ethyl acetate¼9:1); 13% (17.0 mg); colorless
oil; FTIR (NaCl) 3009, 2961, 2928, 1641, 1599, 1464, 1452, 1420, 1406,
1418, 665 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
1.91 (1H, dd, J¼8.1,
13.2 Hz), 2.12 (1H, dd, J¼7.7, 13.3 Hz), 2.34e2.44 (2H, m), 2.38 (3H,
s), 2.55e2.61 (2H, m), 3.50 (1H, dd, J¼7.4, 9.7 Hz), 3.74 (1H, dd,
J¼4.4, 9.7 Hz), 4.23e4.28 (1H, m), 5.01e5.15 (4H, m), 5.55e5.66 (1H,
m), 5.67e5.77 (1H, m), 7.19 (2H, d, J¼7.9 Hz), 7.65 (2H, d, J¼7.9 Hz);
667 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 1.37 (6H, s), 1.73 (1H, dd,
J¼8.4, 12.5 Hz), 2.14 (1H, dd, J¼7.2, 12.5 Hz), 2.37 (3H, s), 4.55 (1H,
dd, J¼7.2, 14.9 Hz), 5.14 (1H, ddd, J¼1.4, 1.4, 10.2 Hz), 5.28 (1H, ddd,
J¼1.4, 1.4, 17.1 Hz), 6.04 (1H, ddd, J¼6.6, 10.2, 17.1 Hz), 7.18 (2H, d,
13C NMR (100 MHz, CDCl3)
d
21.4, 38.0, 39.2, 43.0, 43.4, 69.5, 118.7,
J¼8.1 Hz), 7.66 (2H, d, J¼8.1 Hz); 13C NMR (100 MHz, CDCl3)
d 21.3,
118.8, 127.9, 129.1, 131.8, 133.6, 134.0, 140.1, 177.8; ESIMS: found: m/z
25.9, 27.2, 48.0, 50.3, 69.7, 114.8, 128.0, 128.8, 131.5, 139.7, 140.5,
179.9; ESIMS: found: m/z 294.0861. Calcd for C15H2179BrN: (MþH)þ
294.0857.
332.1018. Calcd for C18H2379BrN: (MþH)þ 332.1014.
4.3.16. 2-(Bromomethyl)-4,4-diphenyl-5-p-tolyl-3,4-dihydro-2H-
pyrrole (4ga). Rf¼0.43 (hexane/ethyl acetate¼9:1); 57% (103.1 mg);
white solid; mp 158e160 ꢀC; FTIR (NaCl) 3019, 2965, 2936, 1638,
4.3.22. 3-(Bromomethyl)-1-p-tolyl-3,4-dihydroisoquinoline
(9a). Rf¼0.20 (hexane/ethyl acetate¼9:1); 64% (70.4 mg); white
solid (mg); mp 80e82 ꢀC; FTIR (NaCl) 3019, 2959, 1607, 1560, 1425,
1599, 1493, 1449, 1423, 669 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 2.25
(3H, s), 2.73 (1H, dd, J¼9.3, 12.9 Hz), 2.99 (1H, dd, J¼6.2, 12.9 Hz),
3.76e3.84 (2H, m), 4.18e4.23 (1H, m), 6.94 (2H, d, J¼7.8 Hz),
7.17e7.40 (10H, m), 7.45 (2H, d, J¼7.5 Hz); 13C NMR (100 MHz,
669 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.40 (3H, s), 2.77 (1H, dd,
J¼12.7, 15.4 Hz), 3.07 (1H, dd, J¼4.7, 15.4 Hz), 3.55 (1H, dd, J¼8.9,
9.3 Hz), 3.78e3.85 (1H, m), 3.88 (1H, dd, J¼4.8, 9.7 Hz), 7.22e7.31
(5H, m), 7.40 (1H, ddd, J¼1.3, 7.2, 7.2 Hz), 7.49 (2H, dd, J¼8.0 Hz); 13C
CDCl3)
d 21.3, 37.3, 53.3, 68.2, 68.7, 126.5, 127.0, 128.3, 128.3, 128.6,
128.7, 129.2, 129.6, 131.2, 140.2, 142.0, 144.6, 176.7; ESIMS: found:
NMR (100 MHz, CDCl3) d 21.4, 30.2, 36.9, 58.5, 126.8, 127.9, 128.2,
m/z 404.1010. Calcd for C24H2379BrN: (MþH)þ 404.1014.
128.8, 128.9, 129.0, 131.0, 135.5, 137.7, 139.7, 167.5; ESIMS: found:
m/z 314.0546. Calcd for C17H1779BrN: (MþH)þ 314.0544.
4.3.17. 3-(Bromomethyl)-1-p-tolyl-2-azaspiro[4.5]dec-1-ene
(4ha). Rf¼0.19 (hexane/ethyl acetate¼9:1); 83% (94.8 mg); yellow
4.3.23. 3-(Bromomethyl)-1-(4-methoxyphenyl)-3,4-dihy-
droisoquinoline (9b). Rf¼0.41 (hexane/ethyl acetate¼9:1); 45%
(56.1 mg); yellow oil; FTIR (NaCl) 3011, 2938,1649,1605,1572,1462,
oil; FTIR (NaCl) 3019, 2930, 1601, 1560, 1447, 664 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
d 1.14e1.85 (11H, m), 2.37 (3H, s), 2.41 (1H, dd,
J¼7.4, 13.1 Hz), 3.62 (1H, dd, J¼7.1, 9.9 Hz), 3.79 (1H, dd, J¼4.0,
1425, 1182, 662 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.76 (1H, dd,
9.9 Hz), 4.32e4.37 (1H, m), 7.18 (2H, d, J¼7.8 Hz), 7.48 (2H, d,
J¼12.7, 15.3 Hz), 3.08 (1H, dd, J¼4.6, 15.3 Hz), 3.55 (1H, dd, J¼8.9,
9.6 Hz), 3.76e3.84 (1H, m), 3.86 (3H, s), 3.88 (1H, dd, J¼4.9, 9.6 Hz),
6.95 (2H, d, J¼8.7 Hz), 7.28 (1H, d, J¼7.9 Hz), 7.32 (2H, dd, J¼6.3,
6.3 Hz), 7.42 (1H, dd, J¼6.3, 7.9 Hz), 7.58 (2H, d, J¼8.7 Hz); 13C NMR
J¼7.8 Hz); 13C NMR (100 MHz, CDCl3)
d 21.3, 23.1, 23.3, 25.5, 32.3,
35.4, 38.4, 39.6, 56.9, 68.9, 128.0, 128.8, 132.4, 139.2, 182.2; ESIMS:
found: m/z 320.1013. Calcd for C17H2379BrN: (MþH)þ 320.1014.
(100 MHz, CDCl3)
d 30.3, 36.8, 55.4, 58.4, 113.6, 126.8, 127.9, 128.3,
4.3.18. 2-(Bromomethyl)-5-p-tolyl-3,4-dihydro-2H-pyrrole
(4ia). Rf¼0.31 (hexane/ethyl acetate¼9:1); 64% (61.5 mg); white
solid; mp 75e77 ꢀC; FTIR (NaCl) 3019, 2961, 1611, 1568, 1456, 1430,
128.8, 130.6, 130.7, 131.0, 137.8, 161.0, 167.0; ESIMS: found: m/z
330.0495. Calcd for C17H1779BrNO: (MþH)þ 330.0494.
669 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
1.86e1.95 (1H, m),
4.3.24. 3-(Bromomethyl)-1-o-tolyl-3,4-dihydroisoquinoline
2.22e2.31 (1H, m), 2.39 (3H, s), 2.89e2.98 (1H, m), 3.05e3.13 (1H,
m), 3.61 (1H, dd, J¼6.6, 10.0 Hz), 3.79 (1H, dd, J¼7.9, 10.0 Hz),
4.54e4.61 (1H, m), 7.22 (2H, d, J¼8.0 Hz), 7.73 (2H, d, J¼8.0 Hz); 13C
(9c). Rf¼0.43 (hexane/ethyl acetate¼9:1); 62% (69.5 mg); colorless
oil; FTIR (NaCl) 3019, 2957, 1612, 1568, 1485, 1454, 1425, 665 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
2.14 (3H, s), 2.89 (1H, dd, J¼12.8,
NMR (100 MHz, CDCl3)
d
21.5, 27.2, 35.5, 38.3, 73.1, 127.8, 129.2,
15.6 Hz), 3.11 (1H, dd, J¼4.9, 15.6 Hz), 3.64 (1H, dd, J¼8.4, 9.3 Hz),
3.89e3.98 (2H, m), 6.94 (1H, d, J¼7.7 Hz), 7.18 (1H, dd, J¼7.5, 7.5 Hz),
7.22e7.34 (5H, m), 7.38 (1H, dd, J¼7.5 Hz); 13C NMR (100 MHz,
131.4, 141.1, 174.4; ESIMS: found: m/z 252.0389. Calcd for
C12H1579BrN: (MþH)þ 252.0388.
CDCl3)
d 19.7, 29.9, 37.2, 58.3, 125.8, 127.2, 127.6, 127.9, 128.5, 128.7,
4.3.19. 4-Bromo-2-(bromomethyl)-5-p-tolyl-3,4-dihydro-2H-pyrrole
(4ia-Br).23. Rf¼0.20 (hexane/ethyl acetate¼9:1); 8% (10.3 mg);
white solid; mp 78e80 ꢀC; FTIR (NaCl) 3015, 2980, 2967,1603,1566,
129.3, 130.4, 131.2, 135.8, 136.3, 138.3, 168.8; ESIMS: found: m/z
314.0550. Calcd for C17H1779BrN: (MþH)þ 314.0544.
1431, 667 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
2.32e2.40 (1H, m),
4.3.25. 3-(Bromomethyl)-1-(2,6-dimethylphenyl)-3,4-dihy-
2.41 (3H, s), 2.67 (1H, dd, J¼6.2, 14.7 Hz), 3.76 (1H, dd, J¼6.2,
droisoquinoline (9d). Rf¼0.36 (hexane/ethyl acetate¼9:1); 53%

596
S. Sanjaya, S. Chiba / Tetrahedron 67 (2011) 590e596
(60.0 mg); brown solid; mp 122e124 ꢀC; FTIR (NaCl) 3017, 2951,1616,
1570,1464,1429, 665 cmꢁ1; 1H NMR (400 MHz, CDCl3)
2.04 (3H, s),
5. For prior studies on iminobromination using NBS, see: (a) Fry, D. F.; Brown, M.;
McDonald, J. C.; Dieter, R. K. Tetrahedron Lett. 1996, 37, 6227; (b) Dechoux, L.;
Jung, L.; Stambach, J.-F. Synthesis 1995, 242.
6. For a report on vanadium haloperoxidase-catalyzed bromocyclization of ter-
penes, see: Carter-Franklin, J. N.; Parrish, J. D.; Tschirret-Guth, R. A.; Little, R. D.;
Butler, A. J. Am. Chem. Soc. 2003, 125, 3688.
7. For a report on bromo- and iodocyclization of alkenyl oximes for the formation
of nitrones, see: Dondas, H. A.; Grigg, R.; Hadjisoteriou, M.; Markandu, J.;
Kennewell, P.; Thornton-Pett, M. Tetrahedron 2001, 57, 1119.
d
2.20 (3H, s), 2.98 (1H, dd, J¼12.7,15.8 Hz), 3.10 (1H, dd, J¼5.4,15.8 Hz),
3.71 (1H, dd, J¼7.9, 10.0 Hz), 3.90 (1H, dd, J¼4.0, 10.0 Hz), 3.99e4.07
(1H, m), 6.87 (1H, d, J¼7.6 Hz), 7.05 (1H, d, J¼7.5 Hz), 7.10 (1H, d,
J¼7.5 Hz), 7.16 (1H, dd, J¼7.6, 7.6 Hz), 7.19 (1H, dd, J¼7.6, 7.6 Hz), 7.29
(1H, d, J¼7.4 Hz), 7.38 (1H, dd, J¼7.4, 7.4 Hz); 13C NMR (100 MHz,
8. Pickard, P. L.; Tolbert, T. L. J. Org. Chem. 1961, 26, 4886.
CDCl3)
d 19.4, 19.5, 29.7, 37.6, 57.9, 126.7, 127.5, 127.6, 127.7, 128.0,
9. Dieter, R. K.; Nice, L. E.; Velu, S. E. Tetrahedron Lett. 1996, 37, 2377.
10. Dewkar, G. K.; Narina, S. V.; Sudalai, A. Org. Lett. 2003, 5, 4501.
11. For reports on PhI(OAc)2-mediated oxidative functionalization of alkenes, see:
(a) Liu, H.; Tan, C.-H. Tetrahedron Lett. 2007, 48, 8220; (b) Fan, R.; Wen, F.; Qin, L.;
Pu, D.; Wang, B. Tetrahedron Lett. 2007, 48, 7444; (c) Margarita, R.; Mercanti, C.;
Parlanti, L.; Piancatelli, G. Eur. J. Org. Chem. 2000, 1865; (d) Kirschning, A.;
Plumeier, C.; Rose, L. Chem. Commun. 1998, 33; (e) Murata, M.; Satoh, K.; Wa-
tanabe, S.; Masuda, Y. J. Chem. Soc., Perkin Trans. 1 1998, 1465; (f) Bruno, M.;
Margarita, R.; Parlanti, L.; Piancatelli, G.; Trifoni, M. Tetrahedron Lett. 1998, 39,
3847; (g) Hashem, A.; Jung, A.; Ries, M.; Kirschning, A. Synlett 1998, 195; (h) De
Mico, A.; Margarita, R.; Mariani, A.; Piancatelli, G. Chem. Commun. 1997, 1237.
12. When PhMgCl was utilized with carbonitrile 1a under the present reaction
conditions, the desired chloromethyl dihydropyrrole 4aa-Cl was obtained in
only 41% yield.
128.1, 128.8, 131.4, 135.3, 135.7, 136.1, 137.8, 168.8; ESIMS: found: m/z
328.0706. Calcd for C18H1979BrN: (MþH)þ 328.0701.
4.3.26. 3-(Bromomethyl)-1-(4-chlorophenyl)-3,4-dihydroisoquino-
line (9e). Rf¼0.39 (hexane/ethyl acetate¼9:1); 59% (72.0 mg);
white solid; mp 81e83 ꢀC; FTIR (NaCl) 3019, 2963, 1607, 1560, 1489,
1427, 669 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
2.78 (1H, dd, J¼12.9,
15.4 Hz), 3.07 (1H, dd, J¼4.6, 15.4 Hz), 3.58 (1H, dd, J¼8.1, 9.5 Hz),
3.78e3.85 (1H, m), 3.88 (1H, dd, J¼4.9, 9.5 Hz), 7.23e7.33 (3H, m),
7.40e7.44 (2H, d, J¼8.4 Hz, 1H, m, overlapped), 7.56 (1H, d,
J¼8.4 Hz); 13C NMR (100 MHz, CDCl3)
d 30.2, 36.8, 58.7, 127.0, 127.9,
13. Tetrahydropyridine
6 was found to be very unstable and decompose to
a complex mixture at room temperature.
128.0, 128.4, 128.5, 130.4, 131.3, 135.8, 136.8, 137.7, 166.6; ESIMS:
found: m/z 334.0000. Calcd for C16H1479Br35ClN: (MþH)þ 333.9998.
14. Brominated NeH imine 7 might be formed via allylic radical bromination, al-
though we are not certain as to the detailed reaction course. For example, it is
speculated that formation of N-bromoimine followed by its thermal hemolytic
cleavage could generate iminyl and bromine radicals as shown below. 1,5-Hy-
drogen shift by radical abstraction of the allylic hydrogen with the iminyl
radical could afford the allylic radical that could be trapped by the resulting
bromine radical to give 7.
4.3.27. 3-(Bromomethyl)-1-(thiophen-2-yl)-3,4-dihydroisoquinoline
(9f). Rf¼0.64 (hexane/ethyl acetate¼9:1); 65% (76.0 mg); yellow
oil; FTIR (NaCl) 3011, 2957, 1601, 1591, 1557, 1520, 1452, 1429,
664 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
2.75 (1H, dd, J¼12.0,
15.2 Hz), 3.07 (1H, dd, J¼4.2, 15.2 Hz), 3.52 (1H, dd, J¼8.7, 9.3 Hz),
3.79e3.88 (2H, m), 7.11 (1H, dd, J¼3.6, 5.0 Hz), 7.35 (2H, dd, J¼7.7,
7.7 Hz), 7.42e7.47 (3H, m), 7.70 (1H, d, J¼7.7 Hz); 13C NMR
Br
Br
H
Br+
N
N
NH
(100 MHz, CDCl3)
d 30.2, 36.2, 58.1, 127.1 (2C, overlapped), 127.3,
Tol
Tol
Tol
Me Me
Me Me
Me Me
127.6, 128.1, 128.4, 128.5, 130.4, 131.3, 135.8, 136.8, 137.7, 166.6;
ESIMS: found: m/z 305.9956. Calcd for C14H1379BrNS: (MþH)þ
305.9952.
Br
NH
Tol
7
Acknowledgements
Me Me
This work was supported by funding from Nanyang Techno-
logical University and Singapore Ministry of Education (Academic
Research Fund Tier 2: MOE2010-T2-1-009).
15. Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070.
16. Semmelhack, M. F.; Le, H. T. M. J. Am. Chem. Soc. 1984, 106, 2715.
17. Donaldson, W. A.; Hossain, M. A.; Cushnie, C. D. J. Org. Chem. 1995, 60, 1611.
18. Yamada, B.; Tagashira, S.; Aoki, S. J. Polym. Sci., Part A: Polym. Chem. 1994, 32,
2745.
References and notes
19. Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748.
20. Wood, M. C.; Leitch, D. C.; Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew. Chem.,
1. (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259; (b) Trost, B. M. Science
1991, 254, 1471.
Int. Ed. 2007, 46,
354.
21. Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2001, 66, 4333.
22. Itou, T.; Yoshimi, Y.; Morita, T.; Tokunaga, Y.; Hatanaka, M. Tetrahedron 2009, 65,
263.
23. Surmont, R.; Verniest, G.; Colpaert, F.; Macdonald, G.; Thuring, J. W.; Deroose,
F.; Kimpe, N. D. J. Org. Chem. 2009, 74, 1377.
2. Wender, P. A.; Croatt, M. P.; Witulski, B. Tetrahedron 2006, 62, 7505.
3. For reviews, see: (a) Frederickson, M.; Grigg, R. Org. Prep. Proced. Int. 1997, 29,
63; (b) Harding, K. E.; Tiner, T. H. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4; p 363.
4. Zhang, L.; Ang, G. Y.; Chiba, S. Org. Lett. 2010, 12, 3682.