Palladium-catalyzed ring-opening of cyclopropyl benzamides: Synthesis of benzo[c]azepine-1-ones via C(sp3)-H functionalization

Article abstract of DOI:10.1016/j.tet.2013.02.080

A variety of difficult to obtain benzo[c]azepine-1-ones are synthesized via a novel palladium-catalyzed, silver-promoted intramolecular cyclization of cyclopropyl benzamides. This biologically important class of molecules is prepared in an efficient and high-yielding manner from easily accessible starting materials. Both aryl bromides and iodides are effective substrates for the transformation. Mechanistic studies indicate that the reaction proceeds through a cyclopropyl C(sp³)-H cleavage step, followed by ring-opening, deprotonation, and reductive elimination.

Full text of DOI:10.1016/j.tet.2013.02.080

Tetrahedron 69 (2013) 4479e4487
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed ring-opening of cyclopropyl benzamides:
synthesis of benzo[c]azepine-1-ones via C(sp3)eH functionalization
*
ꢀ
Carolyn L. Ladd, Daniela Sustac Roman, Andre B. Charette
ꢀ
ꢀ
ꢀ
Centre in Green Chemistry and Catalysis, Department of Chemistry, Universite de Montreal, P.O. Box 6128, Station Downtown, Montreal, QC H3C 3J7,
Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of difficult to obtain benzo[c]azepine-1-ones are synthesized via a novel palladium-catalyzed,
silver-promoted intramolecular cyclization of cyclopropyl benzamides. This biologically important class
of molecules is prepared in an efficient and high-yielding manner from easily accessible starting ma-
terials. Both aryl bromides and iodides are effective substrates for the transformation. Mechanistic
studies indicate that the reaction proceeds through a cyclopropyl C(sp3)eH cleavage step, followed by
ring-opening, deprotonation, and reductive elimination.
Received 30 November 2012
Received in revised form 18 February 2013
Accepted 22 February 2013
Available online 26 February 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Cyclopropane
Palladium catalysis
CeH functionalization
Benzoazepines
Silver
1. Introduction
More recently, Fagnou et al. have disclosed the elegant forma-
tion of quinoline and tetrahydroquinoline derivatives (Scheme 1a).9
The transformation of CeH bonds via palladium catalysis has
emerged as a reliable method for the design of complex chemical
architectures.1 In particular, the direct functionalization of sp2
centers has been well established.2,3 Lately, the activation of the
more challenging sp3 CeH bonds has gained considerable attention
from the organic synthetic community.4,5 The cyclopropyl unit is
a predominant building block in medicinal chemistry, and consid-
erable efforts have been directed toward its synthesis and func-
tionalization.6 Cyclopropanes have unique physical, chemical, and
electronic properties as a result of ring strain; its carbon atoms
display sp2-like properties, which makes them an attractive target
for CeH bond functionalization processes. The research program in
our group has focused on developing novel methodologies aimed
toward the enantioselective synthesis of a variety of substituted
cyclopropanes, as well as their functionalization via metalation and
cross-coupling reactions.7 The opening of cyclopropyl rings is also
a versatile transformation, as it can lead to the formation of com-
plex molecules that are hard to obtain through other means.8
However, the direct CeH functionalization of cyclopropanes re-
mains largely undeveloped in organic synthesis.
The reaction proceeds via Pd(0)-catalyzed cyclopropyl CeH bond
functionalization mediated by pivalate via a concerted metal-
ationedeprotonation (CMD) transition state. This is followed by
ring-opening, deprotonation and finally C(sp2)eC(sp3) bond for-
mation via reductive elimination. The proposed mechanism is
supported by the lack of reaction in the absence of catalytic piv-
alate, a well-known additive in CeH bond activation pathways.10
The tetrahydroquinolines thus formed were prone to de-
composition; consequently, an aromatization protocol to the
* Corresponding author. Tel.: þ1 514 343 6283; fax: þ1 514 343 7586; e-mail
addresses: barbara.bessis@umontreal.ca, andre.charette@umontreal.ca (A.B.
Charette).
Scheme 1. Pd-catalyzed intramolecular cyclopropane opening.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.080

4480
C.L. Ladd et al. / Tetrahedron 69 (2013) 4479e4487
corresponding quinoline species employing 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) as an oxidant was developed.9
Another recent report presents the palladium-catalyzed ring-
opening of aminocyclopropyl Ugi adducts and their subsequent
intramolecular cyclization (Scheme 1b), although it is believed that
this reaction does not proceed through a CeH activation process.11
Other efforts toward the intermolecular activation of cyclopro-
panes have focused on the use of directing groups to guide the
transition metal into the CeH bond.12 A notable example is the
Pd(II)-catalyzed enantioselective direct arylation of cyclopropanes
with boronate esters in the presence of amino acid-derived chiral
ligands, which was disclosed by Yu et al.12b
yield. Omitting Ag3PO4 and adding the phosphate ion in the form of
K3PO4 resulted in trace amounts of the product (entry 7), thus,
further establishing the crucial role of the silver additive. Finally, no
reaction occurred in the absence of the palladium catalyst (entry 8).
Products 2a and 3a were easily separable by column chroma-
tography.17 When the reaction was stopped after 30 min, we ob-
served the formation of 2a in 17% yield, and 3a in 30% yield, along
with recovered starting material. Furthermore, when each isomer
was separately re-submitted to the reaction conditions, benzo[c]
azepine 3a slightly isomerized to 2a (3:1 after 16 h), while no change
was observed for 2a (Scheme 2). This suggests that 3a is the kinet-
ically favored isomer and that 2a is the thermodynamic product.
Due to our long-standing interest in both the synthesis and
functionalization of cyclopropanes, our group has also been explor-
ing various systems that would inducecyclopropyl CeH activation. In
particular, we were interested in direct functionalization of cyclo-
propyl benzamides, such as 1a, as its ring-opening would lead to the
formation of novel seven-membered benzazepine-type products of
particular significance in medicinal chemistry (Scheme 1c).13 These
products are not easily accessible through other routes;14 further-
more, they may serve as precursors to other species, such as ben-
zolactams.15 Herein, we disclose the synthesis of novel benzo[c]
azepine-1-ones via a palladium-catalyzed and silver-promoted ring-
opening of cyclopropyl benzamides and present our mechanistic
investigations that support a C(sp3)eH activation process.
Pd(OAc)2 (5 mol %)
PtBu3•HBF4 (5 mol %)
+
N
N
N
Ag3PO4 (0.33 equiv)
K2CO3 (1.1 equiv)
PhMe, 125 °C, 16 h
O
O
O
3a
3a
2a
3
: 1
same conditions as above
2a
2a
no isomerization
Scheme 2. Isomerization study.
2.2. Scope of the cyclopropane ring-opening reaction
2. Results and discussion
2.1. Reaction optimization
The scope of the transformation was explored using the opti-
mized conditions at 125 ꢀC for 16 h (Table 2). Both aryl bromides
and iodides are efficient substrates for the reaction (entries 1 and
2). Aryl chlorides were not effective under these conditions.18
Substitution on the aromatic ring was well-tolerated, as methyl
groups in both meta and para positions gave excellent yields (en-
tries 3 and 4). Notably, a disubstituted benzamide 1d in both the
ortho and meta positions produced the corresponding products in
a total yield of 94%, demonstrating that steric hindrance adjacent to
the bromide does not impede the reaction (entry 5). The corre-
sponding mono- or difluorinated benzo[c]azepine-1-ones 2eeg
and 3eeg were also obtained in 84e88% overall yields (entries
6e8), indicating that fluorinated aryl substrates are also accessible.
Methoxy substitution on the aromatic ring also gave excellent
conversion (entry 9, 94%). 3,4,5-Trimethoxybenazamide 1i cyclized
to give 17% of the major benzo[c]azepine 2i and 10% of the minor
isomer 3i (entry 10). Starting material and reduced aryl bromide 1i
(30%) were isolated along with the two products (2ie3i). Finally,
replacing the methyl protecting group with a benzyl protecting
group is also viable, producing the corresponding benzo[c]azepines
2j and 3j in a total yield of 96% (entry 11). Interestingly, no product
resulting from direct arylation of the benzyl group was observed,
indicating that the present conditions favor the activation of a cy-
clopropane over an aryl ring. Substitution on the cyclopropane
resulted in low yields as a mixture of isomers.19
We chose cyclopropyl benzamide 1a as our model substrate, as
it is easily accessible from 2-bromobenzoic acid in two steps. We
also hypothesized that the presence of the nitrogen lone pair would
facilitate the opening of the cyclopropane. Screening of the catalyst,
ligand, base and silver salt led to the optimal reaction conditions,
which include Pd(OAc)2 (5 mol %), PtBu3$HBF4 (5 mol %), K2CO3
(1.1 equiv), and Ag3PO4 (0.33 equiv) in toluene at 125 ꢀC (Table 1,
entry 1). We observed the formation of two isomers, 2a and 3a16 in
Table 1
Reaction optimization
Pd(OAc)2 (5 mol %)
PtBu3•HBF4 (5 mol %)
O
+
N
N
N
Ag3PO4 (0.33 equiv)
K2CO3 (1.1 equiv)
PhMe, 125 °C, 16 h
O
2a
O
3a
Br
1a
Entry
Variation from standard conditions
Yield 2a/3a (total)%a
1
2
3
4
5
6
7
8
None
66/26 (92)
18/15b (33)
58/11 (69)
44/9 (53)
47/27 (74)
0/0c(0)
PPh3 instead of PtBu3$HBF4
Ag2CO3 instead of Ag3PO4
AgOAc instead of Ag3PO4
With 0.5 equiv Ag3PO4
Without Ag3PO4
Without Ag3PO4, K3PO4 instead of K2CO3
Without Pd(OAc)2
5/1c(6)
2.3. Mechanistic studies
0/0c(0)
a
1H NMR yield using trimethoxybenzene as internal standard.
Recovery of starting material (27%).
Recovery of starting material (>80%).
Our investigations into the reaction mechanism focused on de-
termining if CeH activation of the cyclopropane occurs prior to
ring-opening, or if the catalyst induces ring-opening.20,21 When
submitting benzamide 1a to the reaction conditions previously
developed by Fagnou et al.,9 we isolated, along with benzo[c]aze-
pine 2a, dihydroisoquinoline 4a in 50% yield and spirooxindole 5a in
18% yield (Scheme 3a). Products 4a and 5a are believed to form via
a pivalate-promoted CMD transition state, each involving CeH ac-
tivation of a different cyclopropane bond, followed by reductive
elimination to give either a five- or a six-membered ring.9,22
b
c
a ratio of 2:1 and total yield of 92%. Replacing air-stable PtBu3$HBF4
with other phosphine ligands, such as PPh3 resulted in incomplete
conversion (entry 2). One equivalent of silver was critical, as no
reaction occurred in its absence (entry 6); also, increasing the silver
loading resulted in diminished yields (entry 5). Other silver sources
were also screened (entries 3 and 4), but Ag3PO4 gave the highest

C.L. Ladd et al. / Tetrahedron 69 (2013) 4479e4487
4481
Table 2
Reaction scope
Entry
Starting
material
Productsa
Yield 2/3
(total)%b
O
N
N
N
N
N
1
66/26 (92)
O
O
O
Br
1a
O
N
I
2a
2a
3a
2
3
4
48/29c (77)
71/27 (98)
62/30 (92)
O
1a’
3a
O
Me
Me
Me
Me
N
N
N
N
N
Me
Me
Br
O
O
O
1b
1c
2b
2c
3b
N
N
O
O
O
Br
O
3c
Me
Me
Me
5
81/13 (94)
N
N
Me
F
Me
F
Br
Me
O
1d
O
2d
2e
2f
3d
N
N
N
6
7
8
9
54/31 (85)
64/24 (88)
69/15 (84)
51/43 (94)
F
F
Br
O
O
1e
3e
O
N
N
N
N
N
N
F
F
O
O
O
Br
1f
3f
O
F
F
F
F
F
F
Br
O
1g
1h
2g
2h
3g
O
MeO
MeO
N
N
N
N
N
N
MeO
Br
O
O
O
3h
OMe
OMe
MeO
MeO
MeO
MeO
MeO
MeO
10
11
17/10d (27)
Br
OMe
O
O
2i
3i
1i
Br Ph
N
O
N
N
59/37 (96)
Ph
Ph
O
O
2j
3j
1j
a
Reaction conditions: Pd(OAc)2 (5 mol %), PtBu3$HBF4 (5 mol %), K2CO3 (1.1 equiv), Ag3PO4 (0.33 equiv), PhMe (0.2 M), 125 ꢀC, 16 h.
Isolated yield.
Dehalogenation also observed (10%).
Dehalogenation and recovered starting material also isolated.
b
c
d

4482
C.L. Ladd et al. / Tetrahedron 69 (2013) 4479e4487
observations indicate that: a) CeH activation of cyclopropanes does
Pd(OAc) (5 mol %)
PtBu Me•HBF (10 mol %)
Br
a.
not require the presence of pivalate; b) acetate is responsible for
proton abstraction via a CMD transition state; and c) ligand struc-
ture may have a more determining effect on product formation and
distribution.26 Studies are currently underway in our laboratory to
further investigate the effects of the ligand and silver additive.
2a
3a
N
N
N
N
CsOPiv (0.3 equiv)
K PO (1.5 equiv)
PhMe, 135 °C, 16 h
0%
10%
O
O
4a
O
5a
1a
50%
18%
Pd(OAc) (5 mol %)
PCy (5 mol %)
Br
b.
c.
4a
5a
15%
2a
3a
Ag3PO (0.33 equiv)
K CO (1.1 equiv)
PhMe, 135 °C, 16 h
39%
24%
22%
2.4. Proposed reaction mechanism
O
1a
Based on our findings, we propose the mechanism shown in
Scheme 4. Oxidative addition of the Pd(0) species into the aryl-
halide bond leads to the formation of intermediate A. Then, ab-
straction of the halide by silver generates cationic species B.
Deprotonation by the acetate ion via CMD transition state C pro-
duces seven-membered palladacycle D,27 followed by cyclopropane
opening, which leads to eight-membered ring palladacycle E. From
intermediate D, there are two possibilities: reductive elimination to
form dihydroisoquinoline 4a, followed by ring-opening to give
isomeric products 2a and 3a, or ring-opening to initially generate
intermediate E, followed by reductive elimination and CeC bond
formation to provide the desired products. The former pathway
was shown to not be plausible under the current reaction condi-
tions using PtBu3$HBF4 as the ligand. Thus, the latter pathway
where ring opening of the cyclopropyl species is aided by both the
Pd catalyst and the nitrogen lone pair may be favored. However,
reductive elimination of palladacycle D does occur predominantly
in presence of PCy3 to give 4a (Scheme 3b).
Pd(OAc) (5 mol %)
PtBu HBF (5 mol %)
4a
no reaction
Ag PO (0.33 equiv)
K CO (1.1 equiv)
PhMe, 125 °C, 16 h
Scheme 3. Mechanistic investigations.
Moreover, when PtBu3$HBF4 was replaced with PCy3 as ligand using
our optimized conditions, products 4a and 5a were also isolated,
albeit in slightly lower yields than the pivalate promoted reaction
(39% and 15%, respectively, Scheme 3b). In light of these experi-
ments, it was hypothesized that dihydroisoquinoline 4a may form
initially in the reaction, and then Pd- or Ag-promoted cyclopropyl
ring-opening may lead to benzo[c]azepines 2a and 3a. However,
when 4a was submitted to the reaction conditions, no ring-opening
of the cyclopropane was observed, and the starting material was
fully recovered (Scheme 3c). In contrast to what was observed by
Fagnou et al.,9 aryl chlorides were not reactive under our optimized
conditions,18 while aryl iodides were feasible substrates (Table 2,
entry 2). Furthermore, when using greater than 1 equiv of silver, the
yield is significantly reduced (Table 1, entry 5). We speculate that
silver abstracts the halide from Pd after the oxidative addition, thus
forming a cationic Pd species.23 Moreover, using a Pd(0) source
resulted in significant loss of yield (14% with 2.5 mol % Pd2(dba)3);
however, the reactivity is restored when an acetate source is added
to the reaction (63%).24 Increasing the amount of ligand in the re-
action did not have a significant effect on yield, while omitting the
ligand resulted in little product formation.25 All these results and
3. Conclusion
In summary, we have disclosed a novel and efficient synthesis of
biologically relevant benzo[c]azepines. Mechanistic investigations
indicate that CeH activation of cyclopropyl moiety occurs prior
to ring opening via a concerted-metalation deprotonation (CMD)
transition state. In contrast to other published methodologies, no
pivalate additive was required. Studies are underway in our group to
expand the scope of direct cyclopropyl CeH functionalizations, in
2a + 3a
1a
Pd0Ln
L
L
Br
AcO
Pd
Pd
O
H
H
N
N
O
Ag+
A
E
AgBr
O
O
L
H
L
2-
3-
Pd
CO3
or
Pd
N
2a + 3a
PO4
N
N
O
O
D
O
4a
H
B
O
O
Pd
with L=PCy3
H
L
OAc-
N
O
C
Scheme 4. Proposed reaction mechanism, L¼PtBu3.

C.L. Ladd et al. / Tetrahedron 69 (2013) 4479e4487
4483
addition to determining the precise role of the ligand and the silver
additive in the reaction.
forming a faint yellow precipitate. The reactionwas stirred overnight
(16 h) at ambient temperature. It was then quenched with 10% HCl
(50 mL), dissolving the white precipitate, and then transferred to
a 250-mL separatory funnel. The layers were separated, and the
aqueous layer was extracted with dichloromethane (3ꢂ’s, 50 mL
each). The combined organics were then washed with brine (50 mL),
dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo to give the desired product as an off-white solid. It was used
crude in the subsequent methylation step.
4. Experimental section
4.1. General considerations
All non-aqueous reactions were run under argon atmosphere
with flame-dried glassware using standard techniques for manip-
ulating air-sensitive compounds.28 Anhydrous solvents were ob-
tained by filtration through drying columns or by distillation over
calcium hydride.
Flash column chromatography was performed using 230e400
mesh silica and Merck type E basic alumina (pH w10e11) by hand
or performed on an automatic purification system using the in-
dicated solvent system (Teledyne Isco CombiflashÒ Rf or Sq16x).
Pre-packed normal phase silica gel columns were used for sepa-
ration of products using Teledyne Isco RediSepÒ Rf High Perfor-
mance Gold or Silicycle SiliaSepTM High Performance columns
(12 g, 24 g, 40 g, or 80 g).
Analytical thin-layer chromatography (TLC) was performed on
pre-coated, glass-backed silica gel plates (Merck 60 F254) and vi-
sualized by UV absorbance (254 nm), and/or ceric ammonium
molybdate (CAM), and potassium permanganate (KMnO4).
Nuclear magnetic resonance spectra were recorded on an
Avance AV400 MHz, Avance AV 300 MHz, or DRX 400 MHz (1H, 13C,
NOE) spectrometer. Chemical shifts for 1H NMR spectra are recor-
ded in parts per million (ppm) from tetramethylsilane (TMS) with
This intermediate was dissolved in 50 mL THF, cooled to 0 ꢀC,
and sodium hydride was added (0.495 g, 12.4 mmol) forming a gray
solution. After 15 min, iodomethane was added dropwise (3.60 mL,
58.0 mmol). The reaction was then warmed to ambient tempera-
ture and stirred overnight (16 h). It was then quenched with water
(50 mL), ethyl acetate was added (50 mL), and transferred to a 250-
mL separatory funnel. The layers were separated, and the aqueous
layer was extracted with ethyl acetate (3ꢂ’s, 50 mL). The combined
organics were washed with brine (50 mL), dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo to give the de-
sired product as a brown oil. The crude was then purified via col-
umn chromatography over silica gel (RediSepÒ Rf Gold 24 g) using
a solvent gradient of 10%e50% ethyl acetate/Hexanes. The desired
product was isolated as a yellow oil (2.09 g, 8.25 mmol, 100% yield).
4.3.1. 2-Bromo-N-cyclopropyl-N-methylbenzamide (1a). Rf: 0.31
(1:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d 7.49e7.44
(m, 1H), 7.29e7.23 (m, 1H), 7.18e7.11 (m, 2H), 3.05 (s, 2.38H),
2.85e2.73 (m, 0.24H), 2.69 (s, 0.63H), 2.67e2.59 (m, 0.80H),
0.84e0.74 (m, 0.86H), 0.41e0.39 (m, 2.93H); 13C NMR (CDCl3,
the solvent resonance as the internal standard (CHCl3,
d
¼7.26 ppm).
The data was reported as follows: chemical shift, multiplicity
(s¼singlet, s (br)¼broad singlet, d¼doublet, dd¼doublet of dou-
blets, dt¼doublet of triplets, td¼triplet of doublets, ddd¼doublet of
doublets of doublets, t¼triplet, q¼quadruplet, br m¼broad multi-
plet, and m¼multiplet), coupling constant in Hertz and integration.
Chemical shifts for 13C NMR spectra were recorded in parts per
million from tetramethylsilane using the central peak of CDCl3
(77.16 ppm) as the internal standard. All 13C NMR spectra were
obtained with complete proton decoupling. The 2-halobenzamides
were reported as a mixture of rotamers.29,30
75 MHz): d 171.1, 170.6, 139.9, 138.9, 132.63, 132.50, 130.1, 129.8,
127.85, 127.71, 127.61, 127.2, 118.98, 118.92, 36.3, 34.0, 31.9, 29.9, 9.3
(br), 7.68 (br), 6.7 (br); FTIR (cmꢁ1) (neat): 3012, 1637, 1455, 1362,
1076, 766; HRMS (APPI, Pos): calcd for C11H13BrNO (MþH)þ:
254.01824, found: 254.0175m/z.
4.3.2. 2-Iodo-N-cyclopropyl-N-methylbenzamide (1a0). The title
compound 1a0 was prepared by the general synthesis on a 12.4 mmol
scale and then purified via column chromatography (20:1 hexanes/
ethyl acetate) to give a light brown oil in 85% yield (3.17 g,10.5 mmol)
over two steps: Rf: 0.53 (1:1 hexanes/ethyl acetate); 1H NMR (CDCl3,
Infrared spectra were taken on a Bruker Vertex Series FTIR (neat)
and are reported in reciprocal centimeters (cmꢁ1). Melting points
400 MHz): d 7.80e7.76 (m, 1H), 7.37e7.32 (m, 1H), 7.19e7.16 (m,1H),
€
were obtained using a Buchi melting point apparatus and are
uncorrected.
7.06e7.00 (m, 1H), 3.10 (s, 2.32H), 2.87e2.84 (m, 0.26H), 2.74 (s,
0.76H), 2.69e2.66 (m, 0.79H), 0.87e0.84 (br m,1.02H), 0.53e0.45 (br
High-resolution mass spectra were performed by the Centre
m, 3.12H); 13C NMR (CDCl3, 75 MHz):
d
171.6, 171.2, 143.2, 142.2,
138.24, 138.12, 129.5, 129.1, 127.8, 127.2, 126.75, 126.58, 126.3, 92.0,
91.7, 77.6, 77.2, 76.7, 36.0, 33.5, 31.6, 29.3, 8.2 (br), 6.0 (br);FTIR (cmꢁ1
ꢀ
ꢀ
ꢀ
regional de spectroscopie de masse de l’Universite de Montreal.
Commercial reagents were used as supplied or purified by
standard techniques where necessary.
)
(neat): 3050, 1634, 1381, 1210, 930; HRMS (APPI, Pos): calcd for
C11H13INO (MþH)þ: 302.00418, found: 302.00363m/z.
4.2. Synthesis of starting materials
4.3.3. 2-Bromo-N-cyclopropyl-N,4-dimethylbenzamide (1b). The ti-
tle compound 1b was prepared by the general synthesis on
a 2.3 mmol scale and then purified via column chromatography
(20:1 hexanes/ethyl acetate) to give a canary yellow solid in 79%
yield (0.49 g, 1.82 mmol) over two steps: mp: 53 ꢀC; Rf: 0.35 (1:1
Starting materials not listed below were obtained commercially
and the reagents were used without further purification.
2-Bromo-3,4,5-trimethoxybenzoic acid31 (used in the synthesis
of 1i) and 2-bromo-3,5-dimethylbenzoic acid32 (used in the syn-
thesis of 1d) were synthesized according to literature procedures.
hexanes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d 7.40 (dd,
J¼8.0, 5.1 Hz, 1H), 7.05e7.00 (m, 2H), 3.10 (s, 2.17H), 2.90e2.86 (m,
0.29H), 2.77 (s, 0.75H), 2.74e2.69 (m, 0.72H), 2.28 (s, 3H), 0.91e0.80
(br m, 1.03H), 0.49e0.47 (m, 2.9H); 13C NMR (CDCl3, 75 MHz)
4.3. General preparation for the synthesis of Benzamides
(1ae1k) (example for 1a shown below)
d
171.3, 170.8, 139.7, 138.7, 137.8, 137.2, 132.3, 131.0, 128.2, 115.58,
To a 100-mL round-bottom flask, flame-dried and cooled under
argon containing 40 mLTHF was added 2-bromobenzoic acid (1.98 g,
8.25 mmol), followed by 2e3 drops of DMF. Oxalyl chloride (1.02 mL,
11.8 mmol) was then slowlyadded over 15 min, causing bubbling and
the formation of a bright yellow solution. The reactionwas stirred for
30 min. To this was added cyclopropylamine (0.8 mL, 11.8 mmol).
After 10 min, triethylamine (3.40 mL, 24.6 mmol) was added slowly,
115.48, 36.3, 32.0, 29.8, 20.8, 9.5 (br), 7.5 (br), 6.8 (br); FTIR (cmꢁ1
)
(neat): 3002, 1635, 1508, 1020, 815, 630, 591; HRMS (APPI, Pos):
calcd for C12H15BrNO (MþH)þ: 268.03396, found: 268.03315m/z.
4.3.4. 2-Bromo-N-cyclopropyl-N,5-dimethylbenzamide (1c). The ti-
tle compound (1c) was prepared by the general synthesis on
a 10.0 mmol scale and then purified via column chromatography

4484
C.L. Ladd et al. / Tetrahedron 69 (2013) 4479e4487
(20:1 hexanes/ethyl acetate) to give a light brown oil in 21% yield
hexanes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d 7.43e7.38 (m,
(0.55 g, 2.05 mmol) over two steps: Rf: 0.34 (1:1 hexanes/ethyl
1H), 7.13e7.07 (m, 1H), 3.08 (s, 2.42H), 2.86e2.85 (m, 0.29H), 2.79
(s, 0.66H), 2.72e2.68 (m, 0.82H), 0.93e0.77 (br m, 0.90H),
acetate); 1H NMR (CDCl3, 400 MHz):
d 7.38 (m, 1H), 7.13 (m, 2H),
3.10 (s, 2.33H), 2.89e2.87 (m, 0.29H), 2.77 (s, 0.68H), 2.72e2.69 (m,
0.79H), 2.34 (s, 3H), 0.90e0.81 (br m, 1H), 0.50e0.47 (br m, 2.96H);
0.55e0.50 (m, 2.91H); 13C NMR (CDCl3, 75 MHz)
d 150.2 (dd,
J¼255.0 Hz, 14.0 Hz), 149.7 (dd, J¼252.0 Hz, 13.0 Hz), 136.8 (t,
J¼5.0 Hz),122.1 (dd, J¼20.0 Hz), 117.0 (dd, J¼20.0 Hz), 113.3 (dd,
J¼4.0, 7.0 Hz), 36.5, 34.4, 32.0, 30.2, 9.0 (br); 19F NMR (282 MHz,
CDCl3): ꢁ133.5 (m), ꢁ134.0 (m), ꢁ136.8 (m), ꢁ137.6 (m); FTIR
(cmꢁ1) (neat): 2924, 1638, 1430, 1293, 887, 797,594; HRMS (APPI,
Pos): calcd for C11H11BrF2NO (MþH)þ: 289.9989, found:
289.99866m/z.
13C NMR (CDCl3, 75 MHz)
d 170.9, 170.5, 140.1, 139.7, 136.7, 135.7,
132.60, 132.49, 128.2, 127.6, 127.3, 127.1, 118.43, 118.36, 36.0, 33.7,
31.6, 29.6, 20.6, 8.2 (br), 6.3 (br), 5.90 (br); FTIR (cmꢁ1) (neat): 2922,
1640, 1380, 1287, 1028, 821, 576; HRMS (APPI, Pos): calcd for
C12H15BrNO (MþH)þ: 268.03403, found: 268.03315m/z.
4.3.5. 2-Bromo-N-cyclopropyl-N,3,5-trimethylbenzamide (1d). The
title compound 1d was prepared by the general synthesis on an
8.1 mmol scale and then purified via column chromatography (20:1
hexanes/ethyl acetate) to give a yellow oil in 83% yield (1.89 g,
6.69 mmol) over two steps:Rf: 0.21 (1:1 hexanes/ethyl acetate); 1HNMR
(CDCl3, 400 MHz): 7.07e6.85 (m, 2H), 3.08 (s, 1.14H), 3.04 (s, 0.70H),
2.91e2.83 (m, 0.26H), 2.74 (s, 0.53H), 2.73e2.64 (m, 0.46H), 2.37e2.26
(m, 6H), 0.88e0.81 (m,1.26H), 0.65e0.55 (br m,1.31H), 0.54e0.39 (br m,
4.3.9. 2-Bromo-N-cyclopropyl-4-methoxy-N-methylbenzamide (1h).
The title compound 1h was prepared by the general synthesis on
a 12.5 mmol scale and then purified via column chromatography
(20:1 hexanes/ethyl acetate) to give a golden oil in 90% yield
(3.20 g, 11.3 mmol) over two steps: Rf: 0.36 (1:1 hexanes/ethyl
acetate); 1H NMR (CDCl3, 400 MHz):
d 7.45e7.40 (m, 1H),
6.79e6.76 (m, 2H), 3.80 (s, 3.83H), 3.11 (s, 3H), 2.91e2.86 (m,
0.51H), 2.80 (s, 1.22H), 2.76e2.73 (m, 1.11H), 0.96e0.81 (m, 3.58H),
0.53e0.50 (m, 2.88H); 13C NMR (CDCl3, 75 MHz) 170.6, 170.2, 158.9,
158.5, 140.4, 139.4, 133.25, 133.08, 116.2, 115.7, 113.1, 112.6, 109.1,
108.9, 55.4, 36.0, 33.8, 31.7, 29.7, 9.1 (br), 7.6 (br), 6.5 (br); FTIR
(cmꢁ1) (neat): 3009, 1638, 1462, 1304, 1235.5, 1014, 815, 597;
HRMS (APPI, Pos): calcd for C12H15BrNO2 (MþH)þ: 284.02867,
found: 284.02807m/z.
2.21H). 13C NMR (CDCl3, 75 MHz)
d 172.1,171.5,140.4,139.4,138.6,138.3,
137.1, 131.8, 131.6, 131.2, 126.0, 125.6, 125.1, 118.1, 36.4, 34.1, 32.1, 30.0,
23.2, 23.2, 21.4, 20.9, 9.7 (br), 7.4 (br), 6.7 (br); FTIR (cmꢁ1) (neat): 3275,
2921, 1672, 1602, 1417, 1113, 963, 835, 637; HRMS (APPI, Pos): calcd for
C13H17BrNO (MþH)þ: 282.04805, found: 282.04880m/z.
4.3.6. 2-Bromo-N-cyclopropyl-4-fluoro-N-methylbenzamide (1e). The
title compound 1e was prepared by the general synthesis on
a 10.0 mmol scale and then purified via column chromatography
(20:1 hexanes/ethyl acetate) to give a cream-colored solid in 87%
yield (2.36 g, 8. 66 mmol) over two steps: mp: 54 ꢀC; Rf: 0.31 (1:1
4.3.10. 2-Bromo-N-cyclopropyl-3,4,5-trimethoxy-N-methylbenza-
mide (1i). The title compound 1i was prepared by the general
synthesis on a 10.0 mmol scale and then purified via column
chromatography (20:1 hexanes/ethyl acetate) to give a light pink
solid in 50% yield (1.70 g, 4.95 mmol) over two steps: mp: 52 ꢀC;
Rf: 0.28 (1:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
hexanes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d 7.32e7.28 (m,
1H), 7.26e7.20 (m, 1H), 7.05 (td, J¼8.0, 3.0 Hz, 1H), 3.09 (s, 2.44H),
2.85 (dt, J¼12.0, 6.0 Hz, 0.21H), 2.76 (s, 0.64H), 2.68 (dt, J¼11.5, 5.5 Hz,
0.82H), 0.90e0.79 (br m, 0.88H), 0.51e0.48 (br m, 3.12H); 13C NMR
d
6.58 (s, 1H), 3.86e3.82 (m, 6H), 3.82e3.81 (m, 3H), 3.07 (s,
(CDCl3, 75 MHz):
d
170.1, 169.6, 161.9 (d, J¼252.0 Hz), 161.7 (d,
2.17H), 2.89e2.82 (m, 3.29H), 2.76 (s, 0.82H), 2.73e2.68 (m,
0.72H), 0.90e0.75 (m, 1.24H), 0.63e0.56 (m, 0.72H), 0.56e0.48
J¼252.0 Hz), 136.1 (d, J¼4.0 Hz) 135.1 (d, J¼4.0 Hz), 129.0 (d,
J¼9.0 Hz), 128.8, 119.8 (d, J¼25.0 Hz), 119.6 (d, J¼25.0 Hz), 119.3 (d,
J¼9.0 Hz), 119.3 (d, J¼9.0 Hz), 115.0 (d, J¼22.0 Hz), 114.4 (d,
J¼22.0 Hz), 36.1, 33.9, 31.7, 29.7, 8.5 (br), 6.5 (br); 19F NMR (CDCl3,
(m, 2.31H); 13C NMR (CDCl3, 75 MHz)
d
171.0, 170.5, 153.6, 153.2,
151.17, 151.06, 143.48, 143.34, 135.5, 134.5, 106.9, 106.4, 105.9, 61.3,
61.3, 56.4, 56.4 36.4, 34.2, 32.0, 30.1, 7.2 (br), 6.5 (br); FTIR (cmꢁ1
)
282 MHz):
d
ꢁ109.9 (m), ꢁ110.4 (m); TIR (cmꢁ1) (neat): 3016, 1637,
(neat): 3263, 3006, 1643, 1421, 1193, 1053, 752, 532; HRMS (APPI,
Pos): calcd for C14H19BrNO4 (MþH)þ: 344.05027,found:
344.0492m/z.
1418, 931, 826; HRMS (APPI, Pos): calcd for C11H12BrFNO (MþH)þ:
272.00868, found: 272.00808m/z.
4.3.7. 2-Bromo-N-cyclopropyl-5-fluoro-N-methylbenzamide(1f). The
title compound 1f was prepared by the general synthesis on
a 2.0 mmol scale and then purified via column chromatography
(20:1 hexanes/ethyl acetate) to give a light pink solid in 32% yield
(0.17 g, 0.63 mmol) over two steps: mp: 52 ꢀC; Rf: 0. 35 (1:1 hexanes/
4.3.11. N-Benzyl-2-bromo-N-cyclopropyl benzamide (1j). Following
the general procedure, the intermediate 2-bromo-N-cyclopropyl
benzamide was benzylated as follows:
To a 50-mL round-bottom flask was added the intermediate
(0.50 g, 2.08 mmol) dissolved in DMF (10 mL). Cs2CO3 (1.35 g,
4.16 mmol, 2.0 equiv) was then added, followed by tetrabuty-
lammonium iodide (TBAI) (77.0 mg, 0.02 mmol, 0.1 equiv). After
stirring for 10 min, benzyl bromide (0.27 mL, 2.29 mmol, 2.0 equiv)
was added to the cloudy cream-colored solution. The reaction was
stirred for 16 h at ambient temperature.
The reaction was then quenched with 25 mL water and trans-
ferred to a 125-mL separatory funnel. The aqueous layer was then
extracted with ethyl acetate (3ꢂ’s, 25 mL each). The combined or-
ganics were then washed with 5% LiCl solution to remove any trace
DMF (25 mL) and with brine (25 mL). The organics were then dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo
to give a brown oil. The crude product was then purified via column
chromatography over silica gel (RediSepÒ Rf Gold 24 g) using
a solvent gradient of 5%e50% ethyl acetate/hexanes. The desired
product 1j was isolated as a yellow oil (0.44 g, 1.49 mmol, 72%
yield): Rf: 0.82 (1:1 hexanes/ethyl acetate); 1H NMR (CDCl3,
ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d 7.51e7.48 (m, 1H),
6.98e6.93 (m, 2H), 3.10 (m, 2.35H), 2.87e2.85 (m, 0.24H), 2.77 (s,
0.59H), 2.72e2.67 (m, 0.79H), 0.90e0.80 (br m, 0.90H), 0.64e0.45
(br m, 3.21H); 13C NMR (CDCl3, 75 MHz): 170.0, 162.1 (d,
J¼249.0 Hz), 161.8 (d, J¼249.0 Hz), 141.7 (d, J¼7.0 Hz), 140.6 (d,
J¼7.0 Hz),134.5 (d, J¼8.0 Hz),134.3 (d, J¼8.0 Hz),117.6 (d, J¼23.0 Hz),
117.4 (d, J¼23.0 Hz), 115.4 (d, J¼24.0 Hz), 115.3 (d, J¼24.0 Hz), 113.6,
36.4, 34.3, 32.0, 30.14, 30.14, 6.94 (br); 19F NMR (CDCl3, 282 MHz):
d
ꢁ113.4 (ddd, J¼8.0, 5.0, 5.0 Hz), ꢁ114.2 (ddd, J¼8.0, 5.0, 5.0 Hz);
FTIR (cmꢁ1) (neat): 2923, 1638, 1433, 1361, 1026, 893, 815, 588;
HRMS (APPI, Pos): calcd for C11H12BrFNO (MþH)þ: 272.00874,
found: 272.00808m/z.
4.3.8. 2-Bromo-N-cyclopropyl-4,5-difluoro-N-methylbenzamide
(1g). The title compound 1g was prepared by the general synthesis
on a 7.8 mmol scale and then purified via column chromatography
(20:1 hexanes/ethyl acetate) to give a light orange solid in 68% yield
(1.55 g, 5.34 mmol) over two steps. mp: 61 ꢀC; Rf: 0.37 (1:1
400 MHz);
d 7.47e7.06 (m, 9H), 4.73e4.61 (br m, 1.16H), 4.63 (s,
0.97H), 4.21 (d, J¼9.5 Hz, 0.30H), 3.18 (br m, 0.43H) 2.62e2.54 (m,

C.L. Ladd et al. / Tetrahedron 69 (2013) 4479e4487
4485
0.14H), 2.48e2.40 (m, 0.0.62H), 0.90e0.30 (m, 3.22H); 13C NMR
(CDCl3, 75 MHz) 171.36, 171.17, 141.1, 139.8, 138.4, 137.6, 136.9,
6.5, 3.9 Hz,1H), 2.30 (ddd, J¼9.6, 8.3, 5.8 Hz,1H),1.34 (ddd, J¼9.8, 6.4,
5.2 Hz, 1H), 0.28e0.24 (m, 1H); 13C NMR (CDCl3, 75 MHz):
161.5,
d
d
132.87, 132.84, 132.80, 130.5, 130.0, 128.75, 128.65, 128.62, 128.58,
128.00, 127.80, 127.67, 127.62, 127.48, 127.35, 127.25, 127.06, 119.5,
119.2, 65.4, 53.2, 50.2, 30.7, 28.6, 9.8 (br), 8.7 (br), 7.0 (br); FTIR
(cmꢁ1) (neat): 3435, 2923, 1639, 1454, 1046, 768, 697, 505; HRMS
(APPI, Pos): calcd for C17H17BrNO (MþH)þ: 330.04932, found:
330.0488m/z.
139.2, 131.8, 129.0, 128.2, 126.6, 125.5, 36.3, 34.9, 15.0, 13.7; FTIR
(cmꢁ1) (neat): 2928, 1621, 1333, 903, 724, 649; HRMS (APPI, Pos):
calcd for C11H12NO (MþH)þ: 174.09139, found: 174.09134m/z.
4.4.3. 20-Methylspiro[cyclopropane-1,10-isoindolin]-30-one (5a). The
title compound 5a was prepared by the general procedure using
PCy3 instead of PtBu3$HBF4 as a ligand at 135 ꢀC to give an orange oil
in 15% yield (13 mg, 0.075 mmol): Rf: 0.11 (1:1 hexanes/ethyl ace-
4.3.12. 2-Chloro-N-cyclopropyl-N-methylbenzamide (1k). The title
compound 1k was prepared by the general synthesis on a 12 mmol
scale and then purified via column chromatography (20:1 hexanes/
ethyl acetate) to give a yellow oil in 91% yield (2.06 g, 9.82 mmol)
over two steps: Rf: 0.58 (1:1 hexanes/ethyl acetate); 1H NMR
tate); 1H NMR (CDCl3, 400 MHz):
d
7.88 (d, J¼7.6 Hz, 1H), 7.52e7.48
(m,1H), 7.42 (td, J¼7.4, 0.7 Hz,1H), 7.05 (d, J¼7.6 Hz,1H), 2.87 (s, 3H),
1.59e1.56 (m, 2H), 1.36e1.33 (m, 2H); 13C NMR (CDCl3, 75 MHz):
d
168.1, 147.2, 131.8, 131.4, 127.4, 123.6, 117.7, 45.1, 24.0, 10.3; FTIR
(CDCl3, 400 MHz):
0.20H), 2.73 (s, 0.58H), 2.70e2.63 (m, 0.79H), 0.81e0.75 (br m,
0.85H), 0.44e0.42 (br m, 3.17H); 13C NMR (CDCl3, 75 MHz):
169.3,
d
7.35e7.22 (m, 4H), 3.07 (s, 2.35H), 2.8e2.83 (m,
(cmꢁ1) (neat): 3502, 2926, 1722, 1591, 1472, 765, 690; HRMS (APPI,
Pos): calcd for C11H12NO (MþH)þ: 174.09137, found: 174.09134m/z.
d
168.9, 137.1, 136.1, 129.3, 129.09, 128.98, 128.63, 128.50, 127.04,
126.86, 126.5, 126.0, 35.2, 33.1, 30.9, 29.0, 7.6 (br), 5.9 (br); FTIR
(cmꢁ1) (neat): 3060, 1637, 1482, 1433, 1319, 859;HRMS (APPI, Pos):
calcd for C11H13ClNO (MþH)þ: 210.06875, found: 210.06802m/z.
4.4.4. 2,7-Dimethyl-2,5-dihydro-1H-benzo[c]azepin-1-one (2b) and
2,7-dimethyl-2,3-dihydro-1H-benzo[c]azepin-1-one (3b). The title
compounds 2b and 3b were prepared by the general procedure to
give a yellow oil in 71% yield (65 mg, 0.35 mmol) and a yellow oil in
27% yield (25 mg, 0.13 mmol): Compound 2b: Rf: 0.55 (1:1 hexanes/
4.4. General procedure for the synthesis of benzo[c]azepin-1-
ones (2ae3j)
ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d 7.68 (s, 1H), 7.17 (d,
J¼8.0 Hz, 1H), 6.95 (dd, J¼7.7, 2.7 Hz, 1H), 5.94 (dd, J¼8.0, 3.0 Hz,
1H), 5.62 (qd, J¼7.0, 3.0 Hz, 1H), 3.27 (s, 3H), 3.17 (dd, J¼7.0, 3.0 Hz,
To a 5.0-mL microwave vial in a glovebox was added in the
following order: Pd(OAc)2 (5.6 mg, 0.025 mmol), PtBu3$HBF4
(7.2 mg, 0.025 mmol), K2CO3 (76.0 mg, 0.55 mmol), and Ag3PO4
(0.16 mmol, 69.1 mg). The vial was crimped shut. The benzamide
(1ae1j) (0.50 mmol) was weighed into a vial, dissolved in 0.5 mL of
toluene and added to the reaction vial. The vial containing benza-
mide was rinsed with 4ꢂ’s 0.5 mL of toluene for a total volume of
2.5 mL. This yellowish-orange solution was then heated to 125 ꢀC in
an oil bath for 16 h. The reaction turned black within 5 min. The
reaction was cooled to ambient temperature, filtered over a cotton-
CeliteÒ plug, and rinsed with 25 mL of ethyl acetate. It was then
concentrated in vacuo to give the crude product. The crude was
then purified via column chromatography over silica gel (RediSepÒ
Rf Gold 24 g) using a solvent gradient of 10%e50% ethyl acetate/
hexanes to give isomers 2ae2j and 3ae3j.
2H), 2.33 (s, 3H); 13C NMR (CDCl3, 75 MHz):
d 169.7, 140.6, 136.3,
133.7, 132.4, 131.6, 130.5, 126.1, 118.1, 36.5, 30.9, 21.0; FTIR (cmꢁ1
)
(neat): 3325, 2952, 1626, 1602, 1405, 1098, 752, 681; HRMS (APPI,
Pos): calcd for C12H14NO (MþH)þ: 188.1079, found: 188.10699m/z.
Compound 3b: Rf: 0.26 (1:1 hexanes/ethyl acetate); 1H NMR (CDCl3,
400 MHz):
J¼9.8 Hz, 1H), 6.34e6.28 (m, 1H), 3.60 (d, J¼6.8 Hz, 2H), 3.21 (s, 3H),
2.40 (s, 3H); 13C NMR (CDCl3, 75 MHz)
168.8, 137.7, 135.2, 134.5,
132.0, 131.28, 131.21, 128.6, 128.4, 46.3,36.3, 21.2; FTIR (cmꢁ1
d 7.82 (s, 1H), 7.23 (s, 1H), 7.11e7.09 (m, 1H), 6.78 (d,
d
)
(neat): 3339, 2921, 1626, 1603, 1391, 835, 713; HRMS (APPI, Pos):
calcd for C12H14NO (MþH)þ: 188.10768, found: 188.10699m/z.
4.4.5. 2,8-Dimethyl-2,5-dihydro-1H-benzo[c]azepin-1-one (2c) and
2,8-dimethyl-2,3-dihydro-1H-benzo[c]azepin-1-one (3c). The title
compounds 2c and 3c were prepared by the general procedure to
give an orange oil in 62% yield (57 mg, 0.31 mmol) and an orange oil
in 30% yield (28 mg, 0.15 mmol): Compound 2c: Rf: 0.52 (1:1 hex-
4.4.1. 2-Methyl-2,5-dihydro-1H-benzo[c]azepin-1-one (2a) and 2-
methyl-2,3-dihydro-1H-benzo[c]azepin-1-one (3a). The title com-
pounds 2a and 3a were prepared by the general procedure to give
an orange oil in 66% yield (58 mg, 0.34 mmol) and an orange oil in
26% yield (23 mg, 0.13 mmol): Compound 2a: Rf: 0.55 (1:1 hexanes/
anes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d
7.76 (d, J¼7.9 Hz,
1H), 7.09 (d, J¼7.9 Hz, 1H), 6.87 (s, 1H), 5.95 (d, J¼7.6 Hz, 1H),
5.63e5.57 (m, 1H), 3.27 (s, 3H), 3.17 (d, J¼7.2 Hz, 2H), 2.34 (s, 3H);
13C NMR (CDCl3, 75 MHz):
d 169.4, 143.2, 142.0, 131.29, 131.11, 130.7,
ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d
7.87e7.84 (m, 1H), 7.37
127.4,126.8,117.5, 36.4, 31.3, 21.3; FTIR (cmꢁ1) (neat): 3332.42, 2921,
1608, 1389, 1282, 1151, 764; HRMS (APPI, Pos): calcd for C12H14NO
(MþH)þ: 188.10778, found: 188.10699m/z. Compound 3c: Rf: 0.15
(td, J¼7.4, 1.4 Hz, 1H), 7.30e7.25 (m, 2H), 7.06 (d, J¼7.6 Hz, 1H), 5.96
(d, J¼7.5 Hz, 1H), 5.62 (q, J¼7.3 Hz, 1H), 3.28 (s, 3H), 3.21 (d,
J¼7.2 Hz, 2H); 13C NMR (CDCl3, 75 MHz):
d
169.5, 143.4, 134.0, 131.6,
(1:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d 7.91 (d,
131.3, 130.7, 126.6, 126.2, 117.8, 36.4, 31.4; FTIR (cmꢁ1) (neat): 2924,
1656, 1364, 1285, 735, 609; HRMS (APPI, Pos): calcd for C11H12NO
(MþH)þ: 174.09141, found: 174.09134m/z. Compound 3a: 1H NMR
J¼8.0 Hz, 1H), 7.19 (d, J¼8.0, 1H), 7.01 (s, 1H), 6.76 (d, J¼10 Hz, 1H),
6.37e6.31 (m, 1H), 3.61 (d, J¼7.0 Hz, 2H), 3.19 (s, 3H), 2.36 (s, 3H);
13C NMR (CDCl3, 75 MHz):
d 169.0, 140.6, 134.78, 134.71, 132.8, 131.2,
(CDCl3, 400 MHz):
d
8.03e8.01 (m, 1H), 7.46e7.36 (m, 2H),
129.5, 128.91, 128.81, 46.4, 36.4, 21.4; FTIR (cmꢁ1) (neat): 3305,
2922, 1621, 1605, 1394, 1064, 832, 755; HRMS (APPI, Pos): calcd for
C12H14NO (MþH)þ: 188.10786, found: 188.10699m/z.
7.22e7.20 (m, 1H), 6.81 (d, J¼9.9 Hz, 1H), 6.41e6.35 (m, 1H), 3.62 (d,
J¼6.8 Hz, 2H), 3.22 (s, 3H); 13C NMR (CDCl3, 75 MHz):
d 168.8, 135.6,
134.7, 131.2, 130.3, 129.8, 128.5, 127.8, 106.2, 46.3, 36.5; FTIR (cmꢁ1
)
(neat): 2923, 1688, 1428, 756, 708, 595; HRMS (APPI, Pos): calcd for
4.4.6. 2,6,8-Trimethyl-2,5-dihydro-1H-benzo[c]azepin-1-one
(2d)
C11H12NO (MþH)þ: 174.09128, found: 174.09134m/z.
and 2,6,8-trimethyl-2,3-dihydro-1H-benzo[c]azepin-1-one (3d). The
title compounds 2d and 3d were prepared by the general pro-
cedure to give an orange oil in 81% yield (72 mg, 0.36 mmol) and
an orange oil in 13% yield (12 mg, 0.59 mmol): Compound 2d: Rf:
0.75 (1:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
4.4.2. 2-Methyl-1a,2-dihydro-1H-cyclopropa[c]isoquinolin-3(7bH)-
one (4a). The title compound 4a was prepared by the general pro-
cedure using PCy3 instead of PtBu3$HBF4 as a ligand at 135 ꢀC to give
an orange oil in 39% yield (34 mg, 0.20 mmol): Rf: 0.42 (1:1 hexanes/
d
7.48 (d, J¼1.0 Hz, 1H), 7.07 (d, J¼1.0 Hz, 1H), 5.98 (d, J¼7.0 Hz,
1H), 5.62 (dt, J¼15.0, 7.0 Hz, 1H), 3.28 (s, 3H), 3.17 (d, J¼8.0 Hz,
2H), 2.33 (s, 3H), 2.29 (s, 3H); 13C NMR (CDCl3, 75 MHz):
170.4,
ethyl acetate); 1H NMR (CDCl3, 400 MHz):
7.44e7.36 (m, 2H), 7.31e7.27 (m, 1H), 3.25 (s, 3H), 3.14 (ddd, J¼8.2,
d
8.15 (d, J¼7.6 Hz, 1H),
d

4486
C.L. Ladd et al. / Tetrahedron 69 (2013) 4479e4487
139.2, 135.6, 134.5, 134.1, 132.3, 130.9, 129.3, 117.6, 36.3, 26.0, 20.9,
19.9; FTIR (cmꢁ1) (neat): 3350, 2920, 1625, 1600, 1385, 1119, 1042,
774, 722; HRMS (APPI, Pos): calcd for C13H16NO (MþH)þ:
202.12355, found: 202.12355m/z. Compound 3d: Rf: 0.15 (1:1
Compound 2g: Rf: 0.54 (1:1 hexanes/ethyl acetate); 1H NMR (CDCl3,
400 MHz):
1H), 5.98 (dt, J¼7.6, 0.9 Hz, 1H), 5.65e5.59 (m, 1H), 3.27 (s, 3H), 3.17
(d, J¼7.2 Hz, 2H); 13C NMR (CDCl3, 75 MHz): 167.3, 152.2 (dd,
J¼227.0, 13.0 Hz), 148.9 (dd, J¼220.0, 13.0 Hz), 140.3 (dd, J¼6.0,
4.0 Hz), 131.0, 130.6 (dd, J¼5.0, 3.5 Hz), 122.0 (d, J¼20.0 Hz), 120.5
(dd, J¼19.0, 1.5 Hz), 117.2, 117.0 (d, J¼20.0 Hz), 115.0 (d, J¼18.0 Hz),
d
7.70 (dd, J¼11.1, 8.2 Hz, 1H), 6.88 (dd, J¼10.2, 7.4 Hz,
hexanes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d 7.60 (td,
J¼0.7, 0.4 Hz, 1H), 7.08 (ddd, J¼1.1, 0.8, 0.5 Hz, 1H), 6.83e6.80 (m,
1H), 6.37e6.31 (m, 1H), 3.56 (d, J¼7.0 Hz, 2H), 3.18 (s, 3H), 2.33 (s,
3H), 2.29 (s, 3H);13C NMR (CDCl3, 75 MHz):
d
169.2, 141.9, 137.6,
36.6, 30.6; 19F NMR (CDCl3, 282 MHz):
d
ꢁ133.3 (m), ꢁ140.8 (m);
136.9, 133.0, 131.7, 128.9, 128.4, 123.0, 46.32, 46.30, 29.8, 21.2,
20.3; FTIR (cmꢁ1) (neat): 3276, 2920, 1629, 1601, 1094, 1035,814;
HRMS (APPI, Pos): calcd for C13H16NO (MþH)þ: 202.12357, found:
202.12264m/z.
FTIR (cmꢁ1) (neat): 3280, 2920, 1658, 1615, 1508, 1439, 1387, 1157,
957, 758, 548; HRMS (APPI, Pos): calcd for C11H10F2NO (MþH)þ:
210.07239, found: 210.0725m/z. Compound 3g: Rf: 0.20 (1:1 hex-
anes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d
7.85 (dd, J¼11.2,
8.2 Hz, 1H), 7.00 (dd, J¼10.7, 7.6 Hz, 1H), 6.70 (d, J¼9.9 Hz, 1H),
4.4.7. 7-Fluoro-2-methyl-2,5-dihydro-1H-benzo[c]azepin-1-one (2e)
and 7-fluoro-2-methyl-2,3-dihydro-1H-benzo[c]azepin-1-one
(3e). The title compounds 2e and 3e were prepared by the general
procedure to give a light yellow oil in 54% yield (51 mg, 0.27 mmol)
and a light yellow oil in 31% yield (29 mg, 0.15 mmol): Compound 2e:
6.42e6.36 (m, 1H), 3.63 (d, J¼6.9 Hz, 1H), 3.19 (s, 3H). 13C NMR
(CDCl3, 75 MHz):
d
166.7, 151.3 (dd, J¼254.0, 13.0 Hz), 149.6 (dd,
J¼252.0, 13.0 Hz), 132.9 (d, J¼1.0 Hz), 132.6 (dd, J¼5.0, 3.0 Hz), 132.1
(dd, J¼7.0, 4.0 Hz), 130.3 (d, J¼2.0 Hz), 120.3 (dd, J¼19.0, 2.0 Hz),
116.7 (d, J¼17.0 Hz), 46.1, 36.5; 19F NMR (CDCl3, 282 MHz):
ꢁ134.1
d
Rf: 0.44 (1:1 hexanes/ethyl acetate);1H NMR (CDCl3, 400 MHz):
d
7.86
(m), ꢁ137.2 (m); FTIR (cmꢁ1) (neat): 3047, 2923, 1626, 1613, 1479,
1278, 886, 818, 754, 606; HRMS (APPI, Pos): calcd for C11H10F2NO
(MþH)þ: 210.07332, found: 210.0725m/z.
(dd, J¼9.0, 6.0 Hz,1H), 6.96e6.96 (m,1H), 6.78e6.75 (m,1H), 5.98 (dt,
J¼8.0, 1.0 Hz, 1H), 5.61e5.59 (m, 1H), 3.27 (s, 3H), 3.19 (d, J¼7.0 Hz);
13C NMR (CDCl3, 75 MHz):
d
168.3, 164.5 (d, J¼252.1 Hz), 145.7 (d,
J¼8.0 Hz),133.7 (d, J¼9.3 Hz),131.0,130.1 (d, J¼3.0 Hz) 116.9,113.6 (d,
4.4.10. 7-Methoxy-2-methyl-2,5-dihydro-1H-benzo[c]azepin-1-one
(2h) and 7-methoxy-2-methyl-2,3-dihydro-1H-benzo[c]azepin-1-one
(3h). The title compounds 2h and 3h were prepared by the gen-
eral procedure to give an orange oil in 51% yield (51 mg,
0.25 mmol) and an orange oil in 43% yield (43 mg, 0.21 mmol):
Compound 2h: Rf: 0.61 (1:1 hexanes/ethyl acetate); 1H NMR
J¼21.3 Hz),113.0 (d, J¼21.8 Hz) 36.3, 31.2; 19F NMR (CDCl3, 282 MHz):
d
ꢁ109.0 (ddd, J¼23.0, 8.0, 6.0 Hz); FTIR (cmꢁ1) (neat): 2922, 1621,
1604, 1276, 1060, 900, 742; HRMS (APPI, Pos): calcd for C11H11FNO
(MþH)þ: 192.08278, found: 192.08192m/z. Compound 3e: Rf: 0.21
(1:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d 8.03 (ddd,
J¼9.0, 6.0, 0.3 Hz, 1.0H), 7.07 (td, J¼8.4, 3.0 Hz, 1H), 6.88 (dd, J¼9.0,
3.0 Hz, 1H), 6.75 (d, J¼10.0 Hz, 1H), 6.44e6.40 (m, 1H), 3.63 (d,
J¼7.0 Hz, 2H), 3.20 (s, J¼2.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
(CDCl3, 400 MHz):
d
7.41 (d, J¼2.0 Hz, 1H), 6.98e6.91 (m, 2H), 5.93
(d, J¼8.0 Hz, 1H), 5.67e5.61 (dt, J¼15.0, 7.0 Hz, 1H), 3.81 (s, 3H),
3.28 (s, 3H), 3.15 (d, J¼7.2 Hz, 2H); 13C NMR (CDCl3, 75 MHz):
d
168.0, 163.5 (d, J¼251.0 Hz), 137.1 (d, J¼8.4 Hz), 133.4, 133.9 (d,
d 169.4, 158.3, 136.0, 134.7, 130.34, 130.29, 127.4, 118.60, 118.44,
J¼2.0 Hz), 133.8, 131.9 (d, J¼2.8 Hz), 130.9, 115.3 (d, J¼21.7 Hz), 114.5
115.0, 55.6, 36.6, 30.4; FTIR (cmꢁ1) (neat): 3328, 1626, 1601, 1282,
1032, 750; HRMS (APPI, Pos): calcd for C12H14NO2 (MþH)þ:
204.10271, found: 204.10191m/z. 3h: Rf: 0.20 (1:1 hexanes/ethyl
(d, J¼21.6 Hz), 46.2, 36.5; 19F NMR (CDCl3, 282 MHz):
d
ꢁ110.3 (dd,
J¼14.6, 8.2 Hz); FTIR (cmꢁ1) (neat):; HRMS (APPI, Pos): calcd for
C11H11FNO (MþH)þ: 192.0817, found: 192.08192m/z.
acetate); 1H NMR (CDCl3, 400 MHz):
d
7.51 (t, J¼2.5 Hz, 1H), 7.12
(dd, J¼8.7, 2.4 Hz, 1H), 7.01e6.98 (m, 1H), 6.76e6.73 (m, 1H),
4.4.8. 8-Fluoro-2-methyl-2,5-dihydro-1H-benzo[c]azepin-1-one (2f)
and 8-fluoro-2-methyl-2,3-dihydro-1H-benzo[c]azepin-1-one
(3f). The title compounds 2f and 3f were prepared by the general
procedure to give a light yellow oil in 64% yield (59 mg, 0.31 mmol)
and a light yellow oil in 24% yield (22 mg, 0.12 mmol): Compound
2f: Rf: 0.55 (1:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
6.27e6.21 (m, 1H), 3.86, 3.60 (d, J¼6.8 Hz, 2H), 3.20 (s, 3H).; 13C
NMR (CDCl3, 75 MHz):
d 168.5, 158.9, 136.7, 134.3, 130.2, 128.0,
127.4, 118.2, 114.2, 55.6, 46.5, 36.4; FTIR (cmꢁ1) (neat): 3356, 2928,
1626, 1601, 1481, 1233, 1030, 789; HRMS (APPI, Pos): calcd for
C12H14NO2 (MþH)þ: 204.10283, found: 204.10191m/z.
d
7.58 (dd, J¼10.0, 3.0 Hz, 1H), 7.10e7.04 (m, 2H), 5.97 (d, J¼7.6 Hz,
1H), 5.69e5.63 (m, 1H), 3.30 (s, 3H), 3.20 (d, J¼7.0 Hz, 2H);
13C
NMR (CDCl3, 75 MHz):
4.4.11. 6,7,8-Trimethoxy-2-methyl-2,5-dihydro-1H-benzo[c]azepin-
1-one (2i) and 6,7,8-trimethoxy-2-methyl-2,3-dihydro-1H-benzo[c]
azepin-1-one (3i). The title compounds 2i and 3i were prepared by
the general procedure to give an orange oil in 17% yield (22 mg,
0.08 mmol) and an orange oil in 10% yield (12.8 mg, 0.05 mmol):
Compound 2i: Rf: 0.58 (1:1 hexanes/ethyl acetate); 1H NMR (CDCl3,
d
d
168.2, 161.4 (d, J¼244.0 Hz), 139.3 (d,
J¼4.0 Hz), 135.6 (d, J¼7.0 Hz), 130.5, 127.8 (d, J¼8.0 Hz), 118.5 (d,
J¼22.0 Hz), 118.0117.9 (d, J¼24.0 Hz),36.5, 30.5; 19F NMR (CDCl3,
282 MHz):
d
ꢁ116.5 (m); FTIR (cmꢁ1) (neat): 3345, 2926, 1625,
1582, 1489, 1321, 719, 545; HRMS (APPI, Pos): calcd for C11H11FNO
400 MHz):
d
7.23 (s, 1H), 5.97 (d, J¼8.0 Hz, 1H), 5.61 (dt, J¼15, 8 Hz,
(MþH)þ: 192.08277, found: 192.08192m/z. Compound 3f: Rf: 0.26
1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.82 (s, 3H), 3.28 (s, 3H), 3.23 (d,
(1:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d
7.72e7.70
J¼7.3 Hz, 2H); 13C NMR (CDCl3, 75 MHz):
d 169.1, 151.6, 148.2, 145.2,
(m, 1H), 7.22e7.11 (m, 2H), 6.77 (d, J¼10.0 Hz, 1H), 6.36e6.33 (m,
131.1, 130.4, 129.5, 118.1, 109.9, 61.0, 56.1, 36.6, 22.2; FTIR (cmꢁ1
)
1H), 3.62 (d, J¼7.0 Hz, 2H), 3.20 (s, 3H); 13C NMR (CDCl3, 75 MHz):
(neat): 2937,1656,1485,1209,1166,1009, 907, 760, 708; HRMS (APPI,
Pos): calcd for C14H18NO4 (MþH)þ: 264.12378, found: 264.12303m/z.
Compound 3i: Rf: 0.20 (1:1 hexanes/ethyl acetate); 1H NMR (CDCl3,
d
167.5, 161.9 (d, J¼249.0 Hz), 137.7 (d, J¼7.0 Hz), 133.8, 131.10 (d,
J¼3.0 Hz), 130.7 (d, J¼8.0 Hz), 129.2, 118.0 (d, J¼22.0 Hz), 117.7 (d,
J¼23.0 Hz), 46.3, 36.5; 19F NMR (CDCl3, 282 MHz):
d
ꢁ113.0
400 MHz): d 7.38 (s, 1H), 7.02e6.99 (m, 1H), 6.36e6.30 (m, 1H),
(m);FTIR (cmꢁ1) (neat): 3271, 2923, 1627, 1606, 1484, 1393, 1026,
756, 557; HRMS (APPI, Pos): calcd for C11H11FNO (MþH)þ:
192.08276, found: 192.08192m/z.
3.96e3.94 (m, 6H), 3.88 (s, 3H), 3.65e3.63 (m, 2H), 3.23 (s, 3H); 13C
NMR (CDCl3, 75 MHz): 169.2, 147.2, 143.0, 136.5, 136.4, 128.5, 128.4,
127.1, 108.9, 60.8, 60.5, 55.6, 46.0, 38.4; FTIR (cmꢁ1) (neat): 2933,
1626, 1195, 1019, 972, 701; HRMS (APPI, Pos): calcd for C14H18NO4
(MþH)þ: 264.12393, found: 264.12303m/z.
4.4.9. 7,8-Difluoro-2-methyl-2,5-dihydro-1H-benzo[c]azepin-1-one
(2g) and 7,8-difluoro-2-methyl-2,3-dihydro-1H-benzo[c]azepin-1-
one (3g). The title compounds 2g and 3g were prepared by the
general procedure to give an orange oil in 69% yield (69 mg,
0.33 mmol) and an orange oil in 15% yield (15 mg, 0.73 mmol):
4.4.12. 2-Benzyl-2,5-dihydro-1H-benzo[c]azepin-1-one (2j) and 2-
benzyl-2,3-dihydro-1H-benzo[c]azepin-1-one (3j). The title com-
pounds 2j and 3j were prepared by the general procedure to give

C.L. Ladd et al. / Tetrahedron 69 (2013) 4479e4487
4487
K.; Baudoin, O. J. Am. Chem. Soc. 2010, 132, 10706e10716; (d) Rousseaux, S.; Gor-
elsky, S. I.; Chung, B. K. W.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 10692e10705.
11. Dos Santos, A.; El Kaïm, L.; Grimaud, L.; Ramozzi, R. Synlett 2012, 438e442.
12. (a) Kubota, A.; Sanford, M. S. Synthesis 2011, 2011, 2579e2589; (b) Wasa, M.;
Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu, J.-Q. J. Am. Chem. Soc. 2011,133,19598e19601.
13. (a) Viti, G.; Giannotti, D.; Altamura, M.; Ricci, R.; Volterra, G.; Lecci, A.; Borsini,
F.; Pestellini, V. Eur. J. Med. Chem. 1993, 28, 439e445; (b) Fan, K.-H.; Lever, J. R.;
Lever, S. Z. Bioorg. Med. Chem. 2011, 19, 1852e1859.
an orange oil in 59% yield (71.9 mg, 0.29 mmol) and an orange oil
in 37% yield (45.5 g, 0.18 mmol): Compound 2j: Rf: 0.78 (1:1
hexanes/ethyl acetate); 1H NMR (CDCl3, 400 MHz):
d 7.92 (dd,
J¼7.7, 1.1 Hz, 1H), 7.41e7.26 (m, 7H), 7.07 (d, J¼7.4 Hz, 1H), 5.99 (d,
J¼7.6 Hz, 1H), 5.67 (q, J¼7.4 Hz, 1H), 4.95 (s, 2H), 3.20 (d, J¼7.2 Hz,
2H); 13C NMR (CDCl3, 75 MHz):
d 169.3, 143.5, 137.6, 133.9, 131.7,
14. For example, via the Schmidt or Beckmann rearrangements: (a) Crosby, I. T.;
Shin, J. K.; Capuano, B. Aust. J. Chem. 2010, 63, 211e226 Other routes: (b) Dinda,
B. K.; Jana, A. K.; Mal, D. Chem. Commun. 2012, 3999e4001; (c) Ye, K.-Y.; Dai, L.-
X.; You, S.-L. Org. Biomol. Chem. 2012, 10, 5932e5939.
131.4, 129.6, 128.8, 128.0, 127.6, 126.7, 126.2, 119.0, 51.8, 31.6; FTIR
(cmꢁ1) (neat): 3060, 3030, 2922, 1619, 1569, 1446, 1311, 724, 698,
463; HRMS (APPI, Pos): calcd for C17H16NO (MþH)þ: 250.12312,
found: 250.12264m/z. Compound 3j: Rf: 0.56 (1:1 hexanes/ethyl
15. (a) Takeuchi, K.; Holloway, W. G.; Mitch, C. H.; Quimby, S. J.; McKinzie, J. H.;
Suter, T. M.; Statnick, M. A.; Surface, P. L.; Emmerson, P. J.; Thomas, E. M.; Siegel,
acetate); 1H NMR (CDCl3, 400 MHz):
d 8.13e8.11 (m, 1H),
€
M. G. Bioorg. Med. Chem. Lett. 2007, 17, 6841e6846; (b) Ortega, R.; Hubner, H.;
7.50e7.30 (m, 7H), 7.24 (d, J¼7.5 Hz, 1H), 6.78 (d, J¼9.9 Hz, 1H),
Gmeiner, P.; Masaguer, C. F. Bioorg. Med. Chem. Lett. 2011, 21, 2670e2674.
6.16e6.12 (m, 1H), 4.85 (s, 2H), 3.60 (d, J¼6.8 Hz, 2H); 13C NMR
16. Structure of the two isomers was determined by 1D NOE experiments.
n.o.e.
(CDCl3, 75 MHz):
d 171.7, 138.0, 134.3, 131.5, 130.5, 129.1, 128.8,
128.7, 128.6, 128.3, 127.9, 127.7, 106.9, 51.9, 43.8; FTIR (cmꢁ1
)
H
H
n.o.e.
n.o.e.
H
(neat): 3064, 3033, 2957, 1629, 1495, 1421, 1277, 797, 700, 474;
HRMS (APPI, Pos): calcd for C17H16NO(MþH)þ: 250.12322, found:
250.12264m/z.
N
N
n.o.e.
O
O
2a
3a
17. Products 2a and 3a can be hydrogenated in the presence of Pd/C
and H2 to give the dehydrogenated product in excellent yield (93%).
Acknowledgements
ꢀ
ꢀ
This work was supported by Universite de Montreal, the Natural
Science and Engineering Council of Canada (NSERC), the Centre for
Green Chemistry and Catalysis, the Canada Research Chair Program
and the Canada Foundation for Innovation. D.S.R. would like to
thank NSERC for a CGS-D scholarship.
18. No reaction was observed for 2-chloro-N-cyclopropyl-N-methylbenzamide,
producing
only
recoverable
starting
material:
Supplementary data
19. An aryl substituent resulted in only 15% isolated yield of a mixture of up to four
isomeric products (with 50% unreacted starting material); heating the reaction
at 120 ꢀC for 3 days increased the yield to 44%
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.02.080.
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ꢀ
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