Synthesis of Medium Ring Nitrogen Heterocycles via a Tandem Copper-Catalyzed C-N Bond Formation-Ring-Expansion Process

Article abstract of DOI:10.1021/ja038565t

A simple method for the preparation of medium ring heterocycles (7-, 8-, 9-, and 10-membered) has been developed. The process employs a Cu-catalyzed coupling of a β-lactam with an aryl bromide or iodide followed by intramolecular attack of a pendant amino group. In some instances, the intermediate β-lactam is observable but can be converted to the aza-heterocycle by catalysis. Acetic acid was found to be superior to transition metal complexes as a catalyst for this ring-expansion process.

Full text of DOI:10.1021/ja038565t

Published on Web 03/02/2004
Synthesis of Medium Ring Nitrogen Heterocycles via a
Tandem Copper-Catalyzed C-N Bond
Formation-Ring-Expansion Process
Artis Klapars, Sean Parris, Kevin W. Anderson, and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received September 17, 2003; E-mail: sbuchwal@mit.edu
Abstract: A simple method for the preparation of medium ring heterocycles (7-, 8-, 9-, and 10-membered)
has been developed. The process employs a Cu-catalyzed coupling of a â-lactam with an aryl bromide or
iodide followed by intramolecular attack of a pendant amino group. In some instances, the intermediate
â-lactam is observable but can be converted to the aza-heterocycle by catalysis. Acetic acid was found to
be superior to transition metal complexes as a catalyst for this ring-expansion process.
Introduction
expansion route to 7-, 8-, 9-, and 10-membered nitrogen
heterocycles.
Medium ring heterocycles are often encountered in biologi-
cally active natural products as well as drug candidates.
However, medium sized rings are difficult to prepare due to
enthalpic and entropic reasons, and direct cyclization methods
are ineffective unless certain conformational restraints are
present in the acyclic precursor.1 A potential solution to the
formation of medium ring heterocycles is to employ a ring
expansion of a â-lactam with a neighboring nitrogen nucleophile.
Banfi and co-workers have elegantly demonstrated such a
possibility for the preparation of 7-membered heterocycles.2
Their work focused on a specific goal related to enzyme
chemistry and required a lengthy synthesis to obtain the needed
substrate.2,3 We felt that N-arylated â-lactams 1 could be readily
accessible using our recently developed copper-catalyzed aryl
amidation reaction, which tolerates a wide range of functional
groups including aliphatic amines, anilines, and certain second-
ary amides.4,5 Herein, we report a general coupling/ring-
Results and Discussion
We set out to test our proposal using 2-bromobenzylamine
and 2-azetidinone as the coupling partners (Table 1, entry 1).
Gratifyingly, the desired 8-membered heterocycle was isolated
in 96% yield and none of the N-arylated â-lactam 1 was
observed, indicating that a facile domino process involving the
C-N coupling and the subsequent ring expansion (eq 1) had
taken place. Interestingly, no ligand was required for the
coupling reaction in entry 1. Presumably, the amino group in
2-bromobenzylamine binds the copper(I) precatalyst, activating
the aryl bromide toward oxidative addition. Although not
investigated in every case, the addition of a diamine ligand,
N,N′-dimethylethylenediamine, was nevertheless found benefi-
cial for many cases in Table 1, particularly when N-substituted
bromobenzylamines were used as coupling partners.
As shown in Table 1, the reaction tolerates substituents on
the â-lactam ring (entry 2), electron-donating groups in the aryl
bromide (entry 3), and an aliphatic OH group (entry 4). If a
norephedrine-derived aryl bromide containing a relatively bulky
N-substituent was used (entry 5), a mixture of the desired
product and the â-lactam intermediate 1 was obtained. To
address this problem, we briefly explored a means to catalyze
the ring-expansion step, which essentially is a transamidation
(1) Reviews: (a) Nubbemeyer, U. Top. Curr. Chem. 2001, 216, 125. (b) Maier,
M. E. Angew. Chem., Int. Ed. 2000, 39, 2073. (c) Evans, P. A.; Holmes,
B. Tetrahedron 1991, 47, 9131. Selected examples: (d) Lindstro¨m, U. M.;
Somfai, P. Chem.-Eur. J. 2001, 7, 94. (e) Biera¨ugel, H.; Jansen, T. P.;
Schoemaker, H. E.; Hiemstra, H.; van Maarseveen, J. H. Org. Lett. 2002,
4, 2673. (f) Derrer, S.; Davies, J. E.; Holmes, A. B. J. Chem. Soc., Perkin
Trans. 1 2000, 2957.
(2) (a) Banfi, L.; Guanti, G.; Rasparini, M. Tetrahedron Lett. 1998, 39, 9539.
(b) Banfi, L.; Guanti, G.; Rasparini, M. Eur. J. Org. Chem. 2003, 1319.
(3) For a different ring-expansion method that utilizes â-lactams to prepare
7-9-membered ring azaheterocycles: Begley, M. J.; Crombie, L.; Daigh,
D.; Jones, R. C. F.; Osborne, S.; Webster, R. A. B. J. Chem. Soc., Perkin
Trans. 1 1993, 2027.
(4) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727. (b) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 7421.
(5) Examples of the use of â-lactams as intermediates in organic synthesis:
(a) Ojima, I. Acc. Chem. Res. 1995, 28, 383. (b) Holton, R. A.; Kim, H.-
B.; Somoza, C.; Liang, F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.;
Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang,
S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc.
1994, 116, 1599. (c) Lee, H. K.; Kim, E.-K.; Pak, C. S. Tetrahedron Lett.
2002, 43, 9641 and references therein. (d) Palomo, C.; Aizpurua, J. M.;
Ganboa, I.; Oiarbide, M. Synlett 2001, 1813. (e) Romo, D.; Rzasa, R. M.;
Shea, H. A.; Park, K.; Langenhan, J. M.; Sun, L.; Akhiezer, A.; Liu, J. O.
J. Am. Chem. Soc. 1998, 120, 12237.
9
10.1021/ja038565t CCC: $27.50 © 2004 American Chemical Society
J. AM. CHEM. SOC. 2004, 126, 3529-3533
3529

A R T I C L E S
Klapars et al.
Table 1. Preparation of 7- and 8-Membered Nitrogen
Table 2. Catalysts for the Ring-Expansion Reaction
Heterocyclesa
amount of
catalyst
entry
catalyst
none
Sc(OTf)3
Sc(OTf)3
Ti(NMe2)4
Ti(NMe2)4
AcOH
time
conversion
yielda
1
2
3
4
5
6
7
8
none
50 mol %
5 mol %
50 mol %
5 mol %
50 mol %
5 mol %
24 h
24 h
24 h
24 h
24 h
3.5 h
16 h
20 h
19%
64%
20%
96%
78%
>99%
>99%
>99%
7%
55%
<5%
<5%
27%
94%
98% (95%)
92%
AcOH
AcOH/TEA
5/10 mol %
a GC yield (isolated yield).
Table 3. Preparation of 9- and 10-Membered Nitrogen
Heterocyclesa
a Performed with 5.0 mol % CuI, 10 mol % N,N′-dimethylethylenedi-
amine, and 2 equiv of K2CO3 in PhMe at 110 °C for 22-24 h. b Isolated
yields (average of two runs); >95% purity as determined by GC and 1H
NMR. c Coupling reaction performed without the ligand. d Transamidation
conditions: 2 equiv of AcOH, THF, 60 °C, 4 h. e Coupling reaction was
performed at 100 °C, 5 h. f Transamidation conditions: 50 mol % Ti(OiPr)4,
dioxane, 110 °C, 24 h.
reaction (eq 1). Several Lewis acid catalysts for intermolecular
transamidation reactions have been recently disclosed by
Gellman and Stahl.6 We found that two of these catalysts, Sc-
(OTf)3 and Ti(NMe2)4, indeed accelerated the ring-expansion
reaction in a model system (Table 2, entries 2-5). We also
found that acetic acid turned out to be even more effective than
the Lewis acidic metal catalysts and slightly better than the 2:1
Et3N/HOAc that had previously been employed (Table 2, entries
6-8).7 Using 2 equiv of AcOH in THF for 4 h at 60 °C, we
were able to convert the crude mixture of the C-N coupling
reaction products obtained in entry 5 (Table 1) into the desired
ring-expanded product.
a Performed with 5.0 mol % CuI, 10 mol % N,N′-dimethylethylenedi-
amine, and 2 equiv of K2CO3 in PhMe at 110 °C for 22-24 h. b Isolated
yields (average of two runs); >95% purity as determined by GC and 1H
NMR. c GC yield. d Coupling reaction was performed without the ligand.
e Transamidation conditions: 10 equiv of AcOH, 10 equiv of NEt3, dioxane,
110 °C, 24 h. f Transamidation conditions: 2 equiv of AcOH, THF, 60 °C,
4 h.
Ti(OiPr)4 in toluene at 110 °C. Interestingly, different catalysts
are optimal for the transamidation reaction of the aniline and
alkylamine nucleophiles, which is most likely due to the
differences in the relative basicity of anilines and alkylamines.
The C-N coupling-ring-expansion reaction could also be
extended to the preparation of 9- and 10-membered rings.
However, direct cyclization of the aryl bromide substrate
providing either an indoline or a tetrahydroquinoline competed
with the desired process (Table 3).8 The ratio of the desired
medium ring product to the undesired 5- or 6-membered ring
side-product exhibited an interesting dependence on the diamine
ligand. Thus, the N,N′-dimethylethylenediamine ligand increased
the yield of the undesired 5-membered heterocycle (Table 3,
entry 1) while decreasing the amount of the undesired 6-mem-
bered heterocycle (Table 3, entry 4). Formation of the 5-mem-
A relatively slow ring-expansion step was also encountered
in the preparation of 7-membered heterocycles starting with
2-haloanilines (Table 1, entries 6-7); less than 5% of the desired
ring expanded product was observed at the end of the copper-
catalyzed coupling reaction. Fortunately, the desired 7-mem-
bered heterocycles could be obtained if the crude mixture of
the coupling reaction products was treated with 50 mol % of
(6) (a) Eldred, S. E.; Stone, D. A.; Gellman, S. H.; Stahl, S. S. J. Am. Chem.
Soc. 2003, 125, 3422. See also: (b) Cheng, J.; Deming, T. J. J. Am. Chem.
Soc. 2001, 123, 9457.
(7) It is important to note that we are only comparing intramolecular
transamidation processes, which are relatively facile as compared to
intermolecular ones. Thus, the dependence on the nature of the catalyst
easily could be different for these two classes of this reaction.
(8) For intramolecular Cu-catalyzed aryl amination reactions, see: Yamada,
K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002, 231.
9
3530 J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004

Cu-Catalyzed C−N Bond Formation−Ring-Expansion Process
A R T I C L E S
mmol, 5.0 mol %), (rac)-4-phenyl-2-azetidinone (177 mg, 1.20 mmol),
and K2CO3 (280 mg, 2.03 mmol), evacuated, and backfilled with argon.
N,N′-Dimethylethylenediamine (11 µL, 0.10 mmol, 10 mol %),
2-bromobenzylamine (125 µL, 1.00 mmol), and toluene (1.0 mL) were
added under argon. The Schlenk tube was sealed with a Teflon valve,
and the reaction mixture was stirred at 110 °C for 25 h in a preheated
oil bath. The resulting yellow suspension was allowed to reach room
temperature, transferred to a solution of 30% aqueous NH3 (5 mL) in
water (20 mL), and extracted with ethyl acetate (3 × 75 mL). The
combined organic layers were dried (Na2SO4) and concentrated by
rotary evaporation. The residue was dissolved in hot ethyl acetate (∼10
mL). To this solution was added hot hexane (∼10 mL), and the product
was allowed to crystallize from the solution in the refrigerator overnight.
The supernatant solution containing some yellow, gelatinous precipitate
was decanted, and the white crystals remaining in the flask were dried
under vacuum to provide the desired product (230 mg, 92% yield).
bered ring side-product was also diminished for an N-benzylated
aryl bromide substrate (Table 3, entries 2 and 3).
Presumably, the N-benzyl substituent decreases the propensity
of the amine to coordinate to the active copper catalyst, thus
preventing the direct cyclization. In some cases (Table 3, entries
39 and 4), the ring-expansion step was relatively slow, and
therefore acetic acid was successfully employed again as a
catalyst. Finally, the structural diversity of the heterocyclic
products accessible via this method could be further expanded
using borane-THF reduction of the amide group (eq 2).
1
mp: 170-171 °C. H NMR (400 MHz, CDCl3): δ 7.45-7.30 (m,
5H), 7.20-7.08 (m, 2H), 6.97 (t, J ) 7.6 Hz, 1H), 6.75 (d, J ) 7.6
Hz, 1H), 6.33 (br s, 1H), 4.56 (dd, J ) 15.4, 8.6 Hz, 1H), 4.41 (dd, J
) 15.4, 6.8 Hz, 1H), 4.26 (dd, J ) 9.8, 2.3 Hz, 1H), 3.71 (s, 1H), 3.30
(dd, J ) 14.0, 9.8 Hz, 1H), 2.94 (dd, J ) 14.0, 2.3 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 174.6, 147.4, 144.9, 130.3, 129.2, 128.9, 128.0,
126.2, 122.7, 122.5, 60.7, 45.8, 45.2. IR (neat, cm-1): 3293, 1654,
1472, 1457, 757, 731, 699. Anal. Calcd for C16H16N2O: C, 76.16; H,
6.39. Found: C, 76.20; H, 6.45.
Conclusion
In summary, we have developed a procedure for the prepara-
tion of 7-, 8-, 9-, and 10-membered nitrogen heterocycles via a
domino process involving a copper-catalyzed C-N coupling
reaction followed by a ring-expansion step proceeding through
an intramolecular transamidation reaction. The simplicity of the
process and the relative lack of methods to prepare 7-10-
membered nitrogen heterocycles should render this method of
great use to synthetic chemists. We have also found that the
transamidation reaction can be efficiently catalyzed by acetic
acid (in the case of alkylamine substrates) or Ti(OiPr)4 (for
aniline substrates). We believe that these catalysts offer a
significant advantage over the previously reported transamida-
tion catalysts in the case of intramolecular processes.
5-[(1R,2S)-2-Hydroxy-1-methyl-2-phenylethyl]-2,3,5,6-tetrahydro-
1H-benzo[b][1,5]-diazocin-4-one (Table 1, Entry 5). A Schlenk tube
was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), 2-azetidinone
(86 mg, 1.21 mmol), and K2CO3 (280 mg, 2.03 mmol), evacuated, and
backfilled with argon. A solution of (1S,2R)-N-(2-bromobenzyl)-
norephedrine (325 mg, 1.01 mmol) in PhMe (1.0 mL) was added under
argon followed by N,N′-dimethylethylenediamine (11 µL, 0.10 mmol,
10 mol %). The Schlenk tube was sealed with a Teflon valve, and the
reaction mixture was stirred at 110 °C for 23 h in a preheated oil bath.
The resulting tan suspension was allowed to reach room temperature,
transferred to a solution of 30% aqueous NH3 (5 mL) in water (20
mL), and extracted with CH2Cl2 (4 × 15 mL). The combined organic
layers were dried (Na2SO4) and concentrated. The crude product mixture
was dissolved in THF (10 mL) and, using a syringe, was transferred to
a Schlenk tube filled with argon and capped with a rubber septum.
Acetic acid (115 µL, 2.01 mmol) was added to the Schlenk tube, the
rubber septum was replaced with a Teflon valve, and the sealed Schlenk
tube was placed in an oil bath preheated to 110 °C. After being stirred
at 60 °C for 4 h, the resulting pale yellow solution was allowed to
reach room temperature, poured into 1 M aqueous Na2CO3 (20 mL),
and extracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were dried (Na2SO4), concentrated, and the residue was purified by
column chromatography on silica gel (CH2Cl2-MeOH 30:1). The
product was dissolved in CH2Cl2 (10 mL) and concentrated to ∼2 mL
followed by addition of hexane (∼15 mL). The resulting crystals were
collected and dried to give the desired product (215 mg, 69% yield) as
fine, white needles. mp: 213-215 °C. 1H NMR (400 MHz, CDCl3): δ
7.27-7.14 (m, 4H), 7.10-7.05 (m, 3H), 6.87 (td, J ) 7.8, 1.4 Hz),
6.71 (dd, J ) 7.8, 1.4 Hz), 5.82 (s, 1H), 4.79 (s, 1H), 4.66 (d, J ) 16.0
Hz, 1H), 4.32 (d, J ) 16.0 Hz, 1H), 4.13 (br t, J ) 5.3 Hz, 1H), 3.60-
3.45 (m, 2H), 3.34-3.27 (m, 1H), 3.10-2.93 (m, 2H), 1.12 (d, J )
7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 175.0, 149.4, 142.9,
131.5, 129.2, 128.0, 126.9, 125.9, 123.0, 120.3, 118.9, 76.4, 65.9, 54.7,
44.2, 39.5, 9.6. IR (neat, cm-1): 3355, 3215, 1618, 1604, 1489, 1472,
1037, 767, 704. Anal. Calcd for C19H22N2O2: C, 73.52; H, 7.14.
Found: C, 73.22; H, 7.13.
Experimental Section
The following are select procedures for the Cu-catalyzed C-N bond
formation-ring-expansion process. A full account of the reaction
conditions and characterization of substrates and products can be found
in the Supporting Information.
2,3,5,6-Tetrahydro-1H-benzo[b][1,5]diazocin-4-one (Table 1, En-
try 1). A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol,
5.0 mol %), 2-azetidinone (177 mg, 1.20 mmol), and K2CO3 (280 mg,
2.03 mmol), evacuated, and backfilled with argon. 2-Bromobenzylamine
(125 µL, 1.00 mmol) and toluene (1.0 mL) were added under argon.
The Schlenk tube was sealed with a Teflon valve, and the reaction
mixture was stirred at 110 °C for 24 h in a preheated oil bath. After
the resulting green-brown suspension was allowed to reach room
temperature, dodecane (46 µL, internal GC standard) and CH2Cl2 (3
mL) were added, and the supernatant solution was analyzed by GC to
indicate >99% conversion of the aryl bromide starting material. The
reaction mixture was filtered through a silica gel plug (0.5 × 0.5 cm)
eluting with 10:1 CH2Cl2-MeOH (50 mL), the filtrate was concen-
trated, and the residue was purified by column chromatography on silica
gel (CH2Cl2-MeOH 20:1) to provide the desired product as a pale
1
yellow solid (167 mg, 95% yield). mp: 109-110 °C. H NMR (400
MHz, CDCl3): δ 7.16-7.09 (m, 2H), 6.90 (td, J ) 7.6, 1.2 Hz, 1H),
6.76 (d, J ) 7.6 Hz, 1H), 6.40 (br s, 1H), 4.37 (d, J ) 7.7 Hz, 2H),
3.94 (br s, 1H), 3.40-3.33 (m, 2H), 2.87-2.81 (m, 2H). 13C NMR
(100 MHz, CDCl3): δ 176.1, 148.9, 130.9, 129.7, 129.2, 122.3, 121.5,
45.7, 45.3, 39.1. IR (neat, cm-1): 3319, 1653, 1604, 1485, 1409, 1093,
756. Anal. Calcd for C10H12N2O: C, 68.16; H, 6.86. Found: C, 68.42;
H, 6.94.
8-Methyl-1,2,3,5-tetrahydropyrido[3,4-b][1,4]diazepin-4-one (Table
1, Entry 7). A Schlenk tube was charged with CuI (9.6 mg, 0.050
mmol, 5.0 mol %), 2-amino-3-bromo-5-methylpyridine (188 mg, 1.01
mmol), 2-azetidinone (86 mg, 1.21 mmol), and K2CO3 (280 mg, 2.03
mmol), evacuated, and backfilled with argon. N,N′-Dimethylethylene-
2-Phenyl-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one (Table
1, Entry 2). A Schlenk tube was charged with CuI (9.6 mg, 0.050
(9) The stereochemistry of the product in Table 3, entry 3, was determined to
be as shown by X-ray crystallography (see Supporting Information).
9
J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004 3531

A R T I C L E S
Klapars et al.
diamine (11 µL, 0.10 mmol, 10 mol %) and toluene (1.0 mL) were
added under argon. The Schlenk tube was sealed with a Teflon valve,
and the reaction mixture was stirred at 110 °C for 23 h in a preheated
oil bath. The resulting brown-black suspension was allowed to reach
room temperature, filtered through a silica gel plug (0.5 × 0.5 cm)
eluting with 10:1 CH2Cl2-MeOH (50 mL), and the red filtrate was
concentrated. The semisolid residue in the evaporation flask (ca. 155
mg) was transferred to a Schlenk tube, which was then evacuated,
backfilled with argon, and sealed with a rubber septum. The evaporation
flask was rinsed with warm toluene (2 + 2 × 1.5 mL) under argon,
and the washings were transferred to the Schlenk tube using a syringe.
Ti(OiPr)4 (148 µL, 0.501 mmol) was added to the Schlenk tube under
argon, the septum on the Schlenk tube was replaced with a Teflon valve
under a stream of argon, and the sealed Schlenk tube was placed in an
oil bath preheated to 110 °C. After being stirred at 110 °C for 24 h,
the reaction mixture was allowed to reach room temperature and then
filtered through a silica gel plug (0.5 × 0.5 cm) eluting with 10:1 CH2-
Cl2-MeOH (50 mL). The filtrate was concentrated, and the residue
was purified by column chromatography on silica gel (CH2Cl2-MeOH
20:1) to provide the desired product as a pink solid (106 mg, 59%
water (20 mL), and extracted with CH2Cl2 (3 × 15 mL). The combined
organic layers were dried (Na2SO4) and concentrated. NMR analysis
of the crude product indicated >99% conversion of the aryl bromide
with ∼90% formation of the unexpanded cis-N-[2-(2-benzylamino)-
ethylphenyl]-3-isopropyl-4-phenyl-2-azetidinone, ∼3% yield of N-
benzylindoline, and only ∼2% yield of the desired 5-benzyl-3-isopropyl-
2-phenyl-1,2,3,5,6,7-hexahydrobenzo[f][1,5]diazonin-4-one. The crude
product mixture was dissolved in dioxane (10 mL) and, using a syringe,
was transferred to a Schlenk tube filled with argon and capped with a
rubber septum. Acetic acid (0.58 mL, 10 mmol) and Et3N (1.4 mL, 10
mmol) were added to the Schlenk tube, the rubber septum was replaced
with a Teflon valve, and the sealed Schlenk tube was placed in an oil
bath preheated to 110 °C. After being stirred at 110 °C for 23 h, the
resulting tan solution was allowed to reach room temperature, poured
into 1 M aqueous Na2CO3 (50 mL), and extracted with CH2Cl2 (3 ×
30 mL). The combined organic layers were dried (Na2SO4), concen-
trated, and the residue was purified by column chromatography on silica
gel (hexanes-ethyl acetate 4:1). The product was recrystallized from
hot hexane (∼5 mL) to provide the desired cis-5-benzyl-3-isopropyl-
2-phenyl-1,2,3,5,6,7-hexahydrobenzo[f][1,5]diazonin-4-one (351 mg,
88% yield) as colorless cubes. mp: 108-111 °C. 1H NMR (400 MHz,
CDCl3): δ 7.40-7.20 (m, 11H), 7.15 (d, J ) 7.6 Hz, 1H), 7.03 (d, J
) Hz, 1H), 6.96 (t, J ) 7.6 Hz, 1H), 5.33 (d, J ) 14.4 Hz, 1H), 4.70
(s, 1H), 4.18 (d, J ) 14.4 Hz, 1H), 3.62-3.45 (m, 3H), 3.10 (dd, J )
15.5, 7.0 Hz, 1H), 2.78 (dd, J ) 15.5, 8.2 Hz, 1H), 2.69 (dd, J ) 10.6,
4.0 Hz, 1H), 2.00-1.86 (m, 1H), 1.01 (d, J ) 6.5 Hz, 3H), 0.77 (d, J
) 6.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 171.8, 146.6, 139.7,
137.6, 134.1, 130.4, 128.7, 128.5, 128.3, 127.6, 127.4, 127.32, 127.26,
123.4, 123.0, 66.3, 53.3, 50.1, 48.2, 34.2, 27.1, 21.9, 20.4. IR (neat,
cm-1): 3368, 1637, 1496, 1447, 757, 731, 699. Anal. Calcd for
C27H30N2O: C, 81.37; H, 7.59. Found: C, 81.38; H, 7.89.
1
yield). mp: 192-194 °C. H NMR (400 MHz, CDCl3): δ 8.52 (br s,
1H), 7.72 (s, 1H), 6.80 (s, 1H), 3.95 (br s, 1H), 3.58-3.49 (m, 2H),
2.86-2.80 (m, 2H), 2.22 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
172.4, 139.0, 136.6, 133.3, 129.5, 126.6, 41.9, 38.3, 17.4. IR (neat,
cm-1): 3354, 3324, 1653, 1605, 1533, 1491, 1394, 1283, 855. Anal.
Calcd for C9H11N3O: C, 61.00; H, 6.26. Found: C, 60.72; H, 6.24.
5-tert-Butyl-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one
(Table 2, Entry 6: Effect of Various Transamidation Catalysts on
the Ring-Expansion Reaction). Two of eight Schlenk tubes were
charged with the following amounts of Sc(OTf)3: 12.3 mg (0.025 mmol,
5 mol %) and 123 mg (0.25 mmol, 50 mol %). All eight Schlenk tubes
were evacuated and backfilled with argon. A solution of 1-[2-(tert-
butylaminomethylphenyl]-2-azetidinone (116 mg, 0.500 mmol) and
dodecane (225 µL, internal GC standard) in toluene (2.5 mL) was added
to each Schlenk tube under argon followed by the following catalysts
in five of the Schlenk tubes: acetic acid, 1.4 µL (0.025 mmol, 5 mol
%) and 14 µL (0.25 mmol, 50 mol %); acetic acid/triethylamine, 1.4
µL of acetic acid (0.025 mmol, 5 mol %)/7.0 µL of triethylamine (0.050
mmol, 10 mol %); and Ti(NMe2)4, 5.8 µL (0.025 mmol, 5 mol %) and
58 µL (0.25 mmol, 50 mol %). The Schlenk tubes were sealed with
Teflon valves, and the reaction mixtures were stirred in a preheated
oil bath at 80 °C and monitored by GC analysis. Ethyl acetate (3 mL)
and 1 M aqueous Na2CO3 (2 mL) were added to each Schlenk tube,
and the organic layer was analyzed by GC. The results are presented
in Table 2. The combined organic layers (Table 2, entry 6) were dried
(Na2SO4) and concentrated by rotary evaporation, and the residue was
purified by column chromatography on silica gel (CH2Cl2-MeOH 10:
1) to provide the desired product as a white solid (110 mg, 95% yield).
2,3,5,6,7,8-Hexahydro-1H-benzo[f][1,5]diazecin-4-one (Table 3,
Entry 4). A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol,
5.0 mol %), 2-azetidinone (86 mg, 1.21 mmol), and K2CO3 (280 mg,
2.03 mmol), evacuated, and backfilled with argon. 3-(2-Bromophenyl)-
propylamine (160 µL, 1.00 mmol), N,N′-dimethylethylenediamine (11
µL, 0.10 mmol, 10 mol %), and toluene (1.0 mL) were added under
argon. The Schlenk tube was sealed with a Teflon valve, and the
reaction mixture was stirred at 110 °C for 23 h in a preheated oil bath.
The resulting tan suspension was allowed to reach room temperature,
transferred to a solution of 30% aqueous NH3 (5 mL) in water (10
mL), and extracted with CH2Cl2 (3 × 15 mL). GC analysis of the extract
indicated >99% conversion of the aryl bromide with ∼13% yield of
1,2,3,4-tetrahydroquinoline. The combined organic layers were dried
(Na2SO4) and concentrated. The crude product mixture was dissolved
in THF (10 mL) and, using a syringe, was transferred to a Schlenk
tube filled with argon and capped with a rubber septum. Acetic acid
(115 µL, 2.01 mmol) was added to the Schlenk tube, the rubber septum
was replaced with a Teflon valve, and the sealed Schlenk tube was
placed in an oil bath preheated to 110 °C. After being stirred at 60 °C
for 4 h, the resulting pale yellow solution was allowed to reach room
temperature, poured into a solution of 30% aqueous NH3 (10 mL) in
water (20 mL), and extracted with CH2Cl2 (3 × 20 mL). The combined
organic layers were dried (Na2SO4), concentrated, and the residue was
purified by column chromatography on silica gel (CH2Cl2-MeOH 20:
1) to provide the desired product (140 mg, 69% yield) as a white solid.
mp: 161-163 °C. The 1H and 13C NMR spectra displayed two sets of
1
mp: 195-198 °C. H NMR (400 MHz, CDCl3): δ 7.05-7.09 (m,
2H), 6.79 (td, J ) 7.4, 0.9 Hz, 1H), 6.62 (d, J ) 7.9 Hz, 1H), 4.68 (s,
2H), 4.05 (br s, 1H), 3.51 (m, 2H), 3.02 (m, 2H), 1.32 (s, 9H). 13C
NMR (100 MHz, CDCl3): δ 173.9, 150.4, 131.7, 128.2, 124.3, 119.5,
118.6, 57.7, 49.1, 44.6, 41.1, 28.6. IR (neat, cm-1): 3426, 1630, 1473,
1415, 1357, 1342, 756. Anal. Calcd for C14H20N2O: C, 72.38; H, 8.68.
Found: C, 72.38; H, 8.75.
cis-5-Benzyl-3-isopropyl-2-phenyl-1,2,3,5,6,7-hexahydrobenzo[f]-
[1,5]diazonin-4-one (Table 3, Entry 3). A Schlenk tube was charged
with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), (rac)-cis-3-isopropyl-4-
phenyl-2-azetidinone (226 mg, 1.20 mmol), and K2CO3 (280 mg, 2.03
mmol), evacuated, and backfilled with argon. N-Benzyl-2-(2-bromophe-
nyl)ethylamine (227 µL, 1.00 mmol), N,N′-dimethylethylenediamine
(11 µL, 0.10 mmol, 10 mol %), and toluene (1.0 mL) were added under
argon. The Schlenk tube was sealed with a Teflon valve, and the
reaction mixture was stirred at 110 °C for 24 h in a preheated oil bath.
The resulting dark purple-gray suspension was allowed to reach room
temperature, transferred to a solution of 30% aqueous NH3 (5 mL) in
1
signals due to rotamers of the cyclic amide in a 2:3 ratio. H NMR
(400 MHz, CDCl3): δ 7.19-7.06 (m, 2H), 6.97 (d, J ) 8.0 Hz, 0.4H),
6.94 (d, J ) 8.0 Hz, 0.6H), 6.87-6.79 (m, 1H), 5.78 (br s, 0.4H), 4.91
(br s, 0.6H), 4.00-3.86 (m, 0.6H), 3.80-3.50 (m, 3.4H), 3.15-2.90
(br m, 1H), 2.80-2.64 (br m, 0.8H), 2.60-2.45 (br m, 1.8H), 2.28 (t,
J ) 5.8 Hz, 1.2 Hz), 2.30-1.82 (br m, 1.8H), 1.74-1.62 (br m, 0.4H).
13C NMR (100 MHz, CDCl3): δ 176.2, 173.5, 147.2, 145.6, 132.5,
131.6, 130.8, 129.0, 128.4, 127.8, 121.5, 121.0, 118.2, 117.2, 45.8,
42.5, 40.9, 40.4, 37.2, 32.4, 32.3, 31.1, 26.9, 24.3. IR (neat, cm-1):
9
3532 J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004

Cu-Catalyzed C−N Bond Formation−Ring-Expansion Process
A R T I C L E S
3372, 3291, 1652, 1583, 1505, 1457, 743. Anal. Calcd for C12H16N2O:
C, 70.56; H, 7.89. Found: C, 70.41; H, 8.03.
funds. We thank Mr. Timothy Barder for determining the crystal
structure of the product in Table 3, entry 3.
Acknowledgment. This paper is dedicated to the memory of
our friend and colleague, Professor Satoru Masamune, in honor
of his seminal contributions to the field of organic chemistry.
We thank the National Institutes of Health (GM 45906) for
supporting this work. We are grateful to Pfizer, Merck, Novartis,
Lundbeck, and Rhodia. We thank the Cambridge-MIT Institute
for support of S.P. and Pharmaceutical solutions for additional
Supporting Information Available: Experimental procedures
and characterization data for all unknown compounds (PDF and
CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA038565T
9
J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004 3533