Intermolecular and regioselective access to polysubstituted benzo- and dihydrobenzo[c]azepine derivatives: Modulating the reactivity of group 6 non-heteroatom-stabilized alkynyl carbene complexes

Article abstract of DOI:10.1002/chem.201400281

We highlight the versatility of non-heteroatom-stabilized tungsten-carbene complexes 3 synthesized in situ, which have been used in a modular approach to access 2-benzazepinium isolable intermediates 5. By employing very mild conditions, benzazepinium derivatives 5 have been obtained in high yield from simple compounds, such as acetylides 2, Fischer-type alkoxycarbenes 1, and phenylimines 4. The process, involving a formal [4+3] heterocycloaddition, occurs in a totally regioselective manner, which differs from the approach previously observed in similar procedures for other carbene analogues. This work, which involves three components, reveals a control of the reactivity of non-heteroatom-stabilized carbene complexes 3 ([4+3] vs. [2+2]- heterocycloaddition reactions) depending on the acetylide substitution pattern. The influence of the substitution pattern in the behavior of the complexes has been computationally analyzed and rationalized. Finally, elaboration of the 2-benzazepinium intermediates allows access to 3H-benzo[c]azepines 6 and 3H-1,2-dihydrobenzo[c]azepines 7-9 with high control of the substitution of the nine positions of the heterocycle.

Full text of DOI:10.1002/chem.201400281

DOI: 10.1002/chem.201400281
Full Paper
&
Heterocycles
Intermolecular and Regioselective Access to Polysubstituted
Benzo- and Dihydrobenzo[c]azepine Derivatives: Modulating the
Reactivity of Group 6 Non-Heteroatom-Stabilized Alkynyl Carbene
Complexes
Jairo Gonzꢀlez,[a] Arꢀnzazu Gꢁmez,[a] Ignacio Funes-Ardoiz,[b] Javier Santamarꢂa,*[a] and
Diego Sampedro[b]
Abstract: We highlight the versatility of non-heteroatom-sta-
bilized tungsten–carbene complexes 3 synthesized in situ,
which have been used in a modular approach to access 2-
benzazepinium isolable intermediates 5. By employing very
mild conditions, benzazepinium derivatives 5 have been ob-
tained in high yield from simple compounds, such as acety-
lides 2, Fischer-type alkoxycarbenes 1, and phenylimines 4.
The process, involving a formal [4+3] heterocycloaddition,
occurs in a totally regioselective manner, which differs from
the approach previously observed in similar procedures for
other carbene analogues. This work, which involves three
components, reveals a control of the reactivity of non-
heteroatom-stabilized carbene complexes 3 ([4+3] vs. [2+2]-
heterocycloaddition reactions) depending on the acetylide
substitution pattern. The influence of the substitution pat-
tern in the behavior of the complexes has been computa-
tionally analyzed and rationalized. Finally, elaboration of the
2-benzazepinium intermediates allows access to 3H-benzo[-
c]azepines 6 and 3H-1,2-dihydrobenzo[c]azepines 7–9 with
high control of the substitution of the nine positions of the
heterocycle.
action with imines,[7d] a process unknown for heteroatom-stabi-
lized analogues. In the course of this study, we observed, as an
unexpected result, a new reaction behavior promoted by
a change in the alkynyl substitution of the non-heteroatom-
stabilized carbene complexes.
Introduction
Benzazepines are a family of heterocycles that have received
special attention due to pharmacological properties exhibited
by several compounds of this family. These compounds have
shown activity against leukemia,[1] HIV,[2] high blood pressure,[3]
and Alzheimer disease[4] among others. As the result of this ac-
tivity, the synthesis of these nitrogenated heterocycles has at-
tracted high interest in recent years. However, although many
intramolecular methodologies have been described, reports of
intermolecular examples of benzazepine synthesis are very
scarce, especially for 2-benzazepine derivatives.[5]
Herein, we report an efficient synthesis of stable benzo[c]a-
zepinium intermediates through a regioselective formal [4+3]
heterocycloaddition of non-heteroatom-stabilized alkynyl(pen-
tacarbonyl)tungsten–carbenes and phenylimines. From this
work, there is an emergence of a remarkable differential reac-
tivity of the alkynyl non-heteroatom-stabilized carbenes that
depends on the aryl[7d] or alkyl substitution at the Cb position
(Scheme 1). The influence of this substitution pattern on the
carbene behavior could be explained and rationalized through
On the other hand, our group has recently moved to non-
heteroatom-stabilized carbenes as a synthetic alternative to
Group 6 Fischer-type carbene complexes[6] due to significant
differences observed in their reactivity.[7] Accordingly, we re-
cently described a formal [2+2] heterocycloaddition in their re-
[a] J. Gonzꢀlez, Dr. A. Gꢁmez, Dr. J. Santamarꢂa
Departamento de Quꢂmica Orgꢀnica e Inorgꢀnica e Instituto Universitario
de Quꢂmica Organometꢀlica “Enrique Moles” Unidad Asociada al C.S.I.C.
Universidad de Oviedo, C./Juliꢀn Claverꢂa, 8, 33006 Oviedo (Spain)
E-mail: jsv@uniovi.es
[b] I. Funes-Ardoiz, D. Sampedro
Departamento de Quꢂmica
Centro de Investigaciꢁn en Sꢂntesis Quꢂmica (CISQ)
Universidad de La Rioja, C./Madre de Dios, 51, 26006 LogroÇo (Spain)
Scheme 1. Synthesis of azetinyl carbenes or benzo[c]azepinium derivatives
from “in situ” generated non-heteroatom-stabilized carbene complexes and
phenylimines.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400281.
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the accomplishment of several computational studies. More-
over, the isolation of azepinium derivatives and further trans-
formation permits access to a family of polysubstituted benzo-
and dihydrobenzo[c]azepine derivatives.
zazepine derivatives with a high control over the substitution
at the four positions of the arene ring (i.e., 5i–q). Thus, the re-
action proceeds in the presence of electron-donating (5j,k) or
electron-withdrawing groups (5l–o). The tolerance to a bro-
mine group (5o) should receive a special mention because the
field to further cross-coupling reactions is opened. Finally, the
use of a cross-conjugated dialkynyl carbene (Table 1, entry h)
reveals a totally selective reaction that leads to the formation
of the azepine ring 5h, instead of the synthesis of the corre-
sponding 2-azetinyl carbene with the participation of the triple
bond with the aryl group (Scheme 1).
Results and Discussion
Synthesis of benzazepinium metalates 5
We started from easy-to-handle corresponding Fischer-type
methoxycarbenes 1 as precursors of non-heteroatom-stabilized
alkynyl carbenes 3. These compounds were synthesized in situ
by the sequential treatment of 1 in THF at À808C with various
From a structural point of view, this [4+3] heterocycloaddi-
tion proceeds with the participation of the imine group as a 1-
azadiene unit in a totally regioselective manner. However, this
regioselectivity is opposite to that previously observed for
formal [4+3]-heterocycloaddition reactions of simple 1-aza-
dienes with chromium[12] heteroatom-stabilized alkynyl carbene
complexes[13] or heterocycloaddition reactions with 1-azadienes
and other a,b-unsaturated carbene or carbenoid derivatives.[14]
acetylides
2
and trimethylsilyl trifluoromethanesulfonate
(TMSOTf).[8] Next, two equivalents of phenylimine 4 were
added to this solution, and the reaction mixture was allowed
to warm to 08C. Removal of the solvent and purification by
column chromatography of the residue afforded benzo[c]aze-
piniumpentacarbonyl tungstenates 5a–q in high overall yield
from Fischer carbenes 1 (Table 1).[9] The structure of the benza-
zepinium rings was determined by NMR spectroscopic (mono-
and bidimensional) analysis and was unambiguously confirmed
by X-ray diffraction studies of a single crystal obtained after re-
crystallization of 5a from a mixture of pentane/CH2Cl2.[10,11] The
high versatility of the reaction in terms of the Fischer carbene
precursor 1 as aryl (5a–f and 5i–q), alkyl (5g), and alkynyl (5h)
carbenes employed can be inferred (Table 1). Additionally, this
versatility can also be observed because a wide family of phe-
nylimines 4 can be used, thus allowing the formation of 2-ben-
Mechanistic studies
A simplified mechanistic proposal for the formation of azepini-
um derivatives 5 is outlined in Scheme 2. Thus, after the regio-
selective attack of imine 4 at Cb on the non-heteroatom-stabi-
lized carbene 3, the allenyl metalate intermediate I could
evolve to form intermediate II through a cyclization step in-
volving a [1,2]-pentacarbonyltungsten shift.[15] Finally, a [1,5]-
Table 1. Synthesis of azepinium derivatives 5.
Compound
R1
R2
R3
R4
R5
R6
R7
Yield [%][a]
5a
5b
5c
5d
5e
5 f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
Ph
Ph
p-Tol
Ph
Ph
c-C3H5
i-C3H7
c-C3H5
c-C3H5
i-C3H7
Bu
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
Bu
Bu
Bu
allyl
allyl
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
88
95
82
71
93
61
29
82
92
94
92
76
86
72
89
75[b]
84
Ph
c-C3H5
Ph-CꢀC
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
OMe
OTBDMS
NO2
CO2Me
CN
H
H
H
Ph
Ph
[a] Overall yield from Fischer carbenes 1 after purification by column chromatography. [b] A 2.8:1 mixture with its isomer (R5 =H; R7 =Me). TBDMS=tert-
butyldimethylsilyl.
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Scheme 2. Mechanistic proposal for the formation of benzo[c]azepiniumpen-
tacarbonyl tungstenates 5.
hydrogen shift and re-aromatization would lead to the forma-
tion of benzo[c]azepinium 5.
To explain the formation of 5 in contrast with the previously
reported synthesis of azetinyl carbenes,[7d] a series of theoreti-
cal calculations were performed by using the density function-
al theory with the M06 functional including the solvent (i.e.,
THF) along the reaction path. Complete reaction-path calcula-
tions were carried out starting from carbenes 3 with a different
substitution to yield the azetinyl carbene or benzazepinium
derivative 5. We chose R2 =Bu or Ph as representative exam-
ples for both paths in 3 (Scheme 1). Both reaction paths share
most of the features (see Figures S1 and S2 in the Supporting
Information).
The reactivity of intermediate I is the key to understanding
the different possibilities found experimentally for the different
carbene complexes. The transition structures (TSs) in both
cases (R2 =Bu or Ph) that lead to the formation of the four-
membered rings have very similar geometrical features (see
Figure S3 in the Supporting Information). In agreement, both
TSs appear with quite similar energies (DE=16.8 and 16.5 kcal
molÀ1 above the starting materials, with the Ph derivative
slightly more stable).
Figure 1. Transition structures that lead to 5 for R2 =Bu (TS I-II_Bu; top) and
R2 =Ph (TS I-II_Ph; bottom). Bond distances are expressed in ꢄ.
above the starting materials) and geometrically very similar.
However, a clear difference was found in the transition struc-
tures that lead to 5. When R2 =Bu, the relevant structure (TS I-
II_Bu) show a geometry without any relevant distortions,
which allows an energy barrier of only 15.2 kcalmolÀ1 (DDE=
1.6 kcalmolÀ1 below the energy of TS I-II_aze_Bu). The forma-
tion of very stable 5 is the reaction driving force. However,
when R2 =Ph, this substituent in TS I-II_Ph appears to be twist-
ed and is not coplanar to the metal moiety and the incipient
seven-membered ring. Due to this geometry, the energy barri-
er is 22.0 kcalmolÀ1 (DDE=5.5 kcalmolÀ1 higher than the com-
peting TS I-II_aze_Ph). Thus, changing the R2 group from Bu
to Ph alters the relative energies of the crucial steps through
the different electronic features of the groups. The formation
of azetinyl carbenes (i.e., TS I-II_aze_Ph) is preferred when
R2 =Ph; in contrast, 5 is the main product (i.e., TS I-II_Bu)
when R2 =Bu.
The main difference among the two reaction paths concerns
the transition structures that lead to the seven-membered-ring
derivatives 5. The transition structure has an energy of
15.2 kcalmolÀ1 above the starting materials in the case of R2 =
Bu, whereas the energy for the TS is 22.0 kcalmolÀ1 for R2 =Ph.
Analysis of the geometries for these two TSs (Figure 1) allows
understanding of this energy difference. In the case of R2 =Ph,
this phenyl group, the metal moiety (which almost completely
migrates), and the incipient seven-membered ring cannot be
accommodated in a completely planar conformation (dihedral
angle=28.98) to account for the energy stabilization through
conjugation. The cross-conjugation nature of this intermediate
avoids efficient stabilization of the TS, which causes an ener-
getic penalty that leads to an increase in energy for this TS. Ac-
cordingly, the path that leads to 5 is clearly hampered by
a higher energy barrier for R2 =Ph.
Once the most accessible TS in each case has been sur-
mounted, the reaction can only proceed with the formation of
the final products along the corresponding path because these
steps are not expected to be reversible due to the high energy
barriers for the back-reactions. In the case of R2 =Bu, the for-
mation of very stable 5 is produced after a hydrogen-atom mi-
gration. These data are in accordance with the experimental
findings and provide a mechanistic explanation of the ob-
A direct comparison of the energetics involved in the reac-
tion of intermediates I is shown in Figure 2. For the paths
taken by the azetinyl carbene, the key transition structures
(TS I-II_aze) were energetically (DE=16.8 and 16.5 kcalmolÀ1
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Figure 2. DFT calculations for the key steps along the reaction path for R2 =Bu (left) and R2 =Ph (right). The preferred transition states and products are
shown in rectangles. The energies given in brackets [kcalmolÀ1] are relative to the starting materials.
served product formation. The key difference between the two
paths (and, thus, the diverse reaction products) is the relative
stability of the TSs that arise at the key steps. For the com-
pounds in which R2 =Ph, the energy difference between the
two reaction paths (DDE=5.5 kcalmolÀ1) should lead to high
selectivity for the azetinyl carbene. However, the preferred
product is the seven-membered ring when R2 =Bu; in this
case, it should be noted that the energy difference between
both paths (DDE=1.6 kcalmolÀ1) is below the computational
error of the method, although a clear trend, in agreement with
the experimental findings, is found. These energy differences
should be present as similar substituents are placed as the R2
group. Therefore, this result can be generalized to other differ-
Scheme 3. Synthesis of benzazepines 6 and dihydrobenzazepines 7.
ent alkyl and aryl substituents.[16]
ums 5a,c by using a one-pot treatment with trifluoromethane-
sulfonic acid (HOTf) followed by nucleophilic hydride addition.
Synthesis of polysubstituted azepines upon transformation
It can be observed from Table 1 that C1 and C4 are the only
of benzazepinium zwitterions 5
two – out of nine – positions of the benzo[c]azepine ring that
Once the synthesis of the azepinium rings could be achieved,
we decided to take advantage of the potential reactivity of
compounds 5 as the next step to access to a family of metal-
free benzo- and dihydrobenzo[c]azepine derivatives.
cannot be controlled by the combination of the Fischer car-
bene 1, acetylide 2, and phenylimine 4 substitution patterns.
However, after proto-demetalation of azepinium 5b, a one-pot
treatment with aryl-, alkyl- or allylmagnesium bromide rises
into the formation of 1-substituted-2,3-dihydro-1H-benzo[c]-
azepines 8a–c as single diastereoisomers[18] (Scheme 4). The
diastereoselectivity of the reaction for the C1 attack emerges
from the shielding effect of the alkyl group placed at C3.
Finally, starting from benzazepinium 5b, functionalization at
the C4 position could also be accessed following the method-
ology developed by Iwasawa and co-workers[19] (Scheme 5);
Thus, N-allylic azepinium metalates 5d,e were transformed
in high yield into 3H-benzo[c]azepines 6a,b through a modifi-
cation of
a
palladium-catalyzed Tsuji–Trost deallylation[17]
(Scheme 3). On the other hand, the nucleophilicity of C4 and
electrophilicity of C1 of azepinium rings 5 allows their transfor-
mation into partially reduced compounds. Thus, 2,3-dihydro-
1H-benzo[c]azepines 7a,b were readily accessed from azepini-
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is, in their reaction with phenylimines, can be accomplished
([4+3] vs. [2+2]), which depend on the substitution of acety-
lide 2. In addition, a rationalization of the results can be ob-
tained from the theoretical data, which should help to under-
stand and control the reaction mechanism and plan subse-
quent modifications of the reaction.
Scheme 4. Diastereoselective synthesis of dihydrobenzazepines 8.
Experimental Section
Synthesis and characterization
General considerations: All the operations were carried out in an
argon atmosphere by using conventional Schlenk techniques. All
common reagents were obtained from commercial suppliers and
were used without further purification, unless otherwise indicated.
THF was distilled from sodium/benzophenone and dichlorome-
thane from calcium hydride in a nitrogen atmosphere prior to use.
Hexane and ethyl acetate were used from commercial suppliers.
TLC analysis was performed on aluminum-backed plates coated
with silica gel 60, with an F254 indicator or neutral aluminum oxide.
Flash column chromatography was carried out on deactivated[21]
silica gel 60 (230–400 mesh) or silica gel 60 (230–400 mesh). High-
resolution mass spectra were determined on a Finnigan MAT95
spectrometer. NMR spectra were run on Bruker AV-300, DPX-300,
AV-400, or AMX-400 spectrometer with CDCl3 or CD2Cl2 as solvents.
Melting points were performed with a Gallenkamp instrument.
General experimental procedure for the preparation of benzo-
[c]azepiniums
5a–q:
Tungsten–alkoxycarbene
complexes
1 (0.5 mmol) were added to a freshly prepared solution of lithium
acetilyde 2 (0.72 mmol (1.5 mmol for the synthesis of 5 g); acety-
lene (0.75 mmol), butyllithium (0.72 mmol; 1.6m in hexane)) in THF
(40 mL) in an argon atmosphere at À808C. The reaction mixture
was stirred for 15 min at that temperature and TMSOTf (0.18 mL,
0.9 mmol) was added to form the non-heteroatom-stabilized metal
carbenes 3 (blue solution, except for the synthesis of 5 g (pale
red)). At this point, phenylamine 4 (1 mmol) was added to the re-
action mixture, which was allowed to warm until a color change
was observed (approximately À50–08C). Removal of the solvents
under reduced pressure followed by column chromatography of
the residue on deactivated silica gel yielded the corresponding
benzo[c]azepiniumpentacarbonyl tungstenates 5.
Scheme 5. Selective access to 4-substituted dihydrobenzazepines 9.
thus, methoxycarbonylation of 5b followed by selective hy-
dride addition rises into the formation of functionalized dihy-
drobenzazepine 9a. In a similar approach, the use of piperi-
dine instead of methanol allows the aminocarbonylation of
5b, thus resulting in the direct introduction of an amide group
at that position.[20] After the corresponding reduction step, di-
hydrobenzazepine 9b was isolated. Finally, dihydrobenzaze-
pine 9c could also be obtained in high yield through direct hy-
droxymethylenation of 5b when the reaction was performed
in the absence of a nucleophile in the first step.
Experimental data for [(2-butyl-3-cyclopropyl-5-phenyl-3H-ben-
zo[c]azepin-2-ium)-4-yl]pentacarbonyl tungstenate (5a) as
a model compound: Red solid, m.p. 1098C (dec.), yield=88%, Rf =
0.13 (hexane/ethyl acetate 3:1). 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=8.34 (s, 1H), 7.65–7.17 (m, 7H), 7.13 (d, J(H,H)=8.0 Hz,
1H), 6.87 (d, J(H,H)=6.4 Hz, 1H), 4.54 (m, 1H), 4.31 (m, 1H), 2.47
(m, 1H), 2.38 (d, J(H,H)=10.1 Hz, 1H), 2.10 (m, 2H), 1.60 (m, 2H),
1.10 (t, J(H,H)=7.3 Hz, 3H), 1.05 (m, 1H), 0.88 (m, 1H), 0.36 (m,
1H), 0.17 ppm (m, 1H); 13C NMR (75 MHz, CDCl3, 258C): d=204.7
(C), 203.2 (C), 184.8 (C), 158.2 (CH), 154.6 (C), 149.4 (C), 146.5 (C),
133.0 (CH), 132.6 (CH), 131.7 (CH), 131.3 (CH), 130.8 (CH), 128.5
(CH), 128.3 (CH), 126.5 (CH), 126.1 (C), 125.1 (CH), 82.3 (CH), 55.3
(CH2), 32.0 (CH2), 19.8 (CH2), 17.5 (CH), 13.7 (CH3), 6.9 (CH2), 5.7 ppm
(CH2); HRMS (EI) calcd for C23H25N [MÀW(CO)5 +H]: 316.2060;
found: 316.2049.
Conclusion
We have established a smooth, simple, and efficient protocol
for the intermolecular and regioselective access to polysubsti-
tuted stable benzo[c]azepinium compounds in a three-compo-
nent approach. From these compounds, a family of benzo-
and dihydrobenzo[c]azepines was selectively synthesized with
high control over the substitution at all nine positions of the
molecule. On the other hand, these results prove the synthetic
applicability of Group 6 non-heteroatom-stabilized alkynyl car-
bene complexes as an alternative to their Fischer-type ana-
logues. The work reported herein represents the first hetero-
cyclization of this type of compound that involves the partici-
pation of the carbene carbon atom. In addition, these, until re-
cently, elusive complexes have emerged as modulable com-
pounds because two different heterocyclization reactions, that
General experimental procedure for the preparation of 3H-ben-
zo[c]azepines 6a,b: N,N-Dimethylbarbituric acid (78 mg,
0.5 mmol), triethylamine (37 mL, 0.5 mmol), and tetrakistriphenyl-
phosphine palladium(0) (7 mg, 5% mol, 0.0125 mmol) were added
to a solution of benzazepiniums 5d,e (0.25 mmol) in dichlorome-
thane (10 mL). The reaction mixture was heated to reflux until all
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the starting materials had disappeared (a few minutes). After evap-
oration of the solvent under vacuum and filtration of the residue
through a short pad of silica gel, dry toluene (10 mL) was added in
a nitrogen atmosphere to the reaction mixture, which was stirred
at 908C for 4 h (6a) or 12 h (6b). Final evaporation of the solvent
and purification by column chromatography on silica gel yielded
the corresponding 2-benzo[c]azepines 6.
14.0 ppm (CH3); HRMS (EI) calcd for C29H33N [M]: 395.2613; found:
395.2616.
Experimental procedure for the preparation of 4-methoxycar-
bonyl-2,3-dihydro-1H-2-benzo[c]azepine 9a: Methanol (242 mL,
6 mmol), triethylamine (209 mL, 1.5 mmol), and iodine (171 mg,
0.675 mmol) were sequentially added to a solution of benzazepini-
um 5b (96 mg; 0.15 mmol) in THF (15 mL) at À808C. The reaction
mixture was allowed to warm to À308C, and the solvents were re-
moved under reduced pressure. Next, the residue was redissolved
in THF (15 mL) and the solution was cooled to À608C. l-Selectride
in THF (0.975 mL, 1m, 0.975 mmol) was added at this temperature
to the reaction mixture, which was allowed to warm to 08C. Finally,
the solvents were removed under reduced pressure and the resi-
due purified by column chromatography on silica gel (hexane/
ethyl acetate 20:1) to obtain benzazepine 9a (37 mg, 66%).
Experimental data for 3-cyclopropyl-5-phenyl-3H-benzo[c]aze-
pine (6a) as a model compound: Pale-yellow oil, yield=94%, Rf =
0.16 (hexane/ethyl acetate 10:1). 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=8.48 (d, J(H,H)=2.1 Hz, 1H), 7.60 (dd, J(H,H)=7.0 and
1.9 Hz, 1H), 7.50–7.20 (m, 8H), 6.16 (t, J(H,H)=4.2 Hz, 1H), 2.0 (m,
1H), 1.59 (m, 1H), 0.69 (m, 2H), 0.37 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3, 258C): d=160.3 (CH), 141.4 (C), 141.4 (C), 139.2
(C), 136.1 (C), 133.2 (CH), 130.1 (CH), 129.2 (CH), 129.0 (CH), 128.8
(CH), 128.2 (CH), 127.6 (CH), 126.8 (CH), 62.3 (CH), 16.6 (CH), 2.9,
(CH2), 2.2 ppm (CH2); HRMS (EI) for C19H17N [M]: 259.1361; found:
259.1355.
2-Butyl-3-isopropyl-4-methoxycarbonyl-5-phenyl-2,3-dihydro-
1H-benzo[c]azepine (9a): Colorless oil, yield=66%, Rf =0.50
1
(hexane/ethyl acetate 20:1). H NMR (300 MHz, CDCl3, 258C, TMS):
General experimental procedure for the preparation of 2,3-dihy-
dro-1H-2-benzo[c]azepines 7a,b: Trifluoromethanesulfonic acid
(27 mL, 0.3 mmol) was added over a solution of benzazepiniums
5a,c (0.25 mmol) in THF (10 mL) at 08C. After the reaction mixture
changed from red to yellow, a solution of l-selectride in THF
(33 mL, 1.0m, 0.33 mmol) was added, and the reaction mixture was
stirred at 08C for 15 min. Removal of the solvents under reduced
pressure and purification by column chromatography on silica gel
led to the isolation of 2,3-dihydro-1H-2-benzo[c]azepines 7a,b.
d=7.45–7.15 (m, 9H), 6.80 (d, J(H,H)=7.7 Hz, 1H), 3.70 (d, J(H,H)=
10.4 Hz, 1H), 3.54 (d, J(H,H)=10.4 Hz, 1H), 3.44 (s, 3H), 3.15 (d,
J(H,H)=10.1 Hz, 1H), 2.67 (m, 2H), 1.62 (m, 2H), 1.35 (m, 1H), 0.95
(t, J(H,H)=7.1 Hz, 3H), 0.86 (d, J(H,H)=6.0 Hz, 3H), 0.74 (d, J(H,H)=
5.7 Hz, 3H), 0.70 ppm (m, 1H); 13C NMR (75 MHz, CDCl3, 258C): d=
172.2 (C), 147.6 (C), 141.7 (C), 141.4 (C), 138.9 (C), 132.0 (C), 129.3
(CH), 129.2 (CH), 129.1 (CH), 128.8 (CH), 128.0 (CH), 127.9 (CH),
127.3 (CH), 69.8 (CH), 58.7 (CH2), 55.8 (CH2), 51.6 (CH3), 31.5 (CH),
30.1 (CH2), 21.0 (CH2), 20.5 (CH2), 19.9 (CH2), 14.1 ppm (CH2); HRMS
(EI) calcd for C2H2NO2 [MÀH]: 376.2277; found: 376.2278.
Experimental procedure for the preparation of 4-(piperidine-1-
carbonyl)-2,3-dihydro-1H-2-benzo[c]azepine (9b): Piperidine
(887 mL, 9 mmol), triethylamine (418 mL, 3 mmol), and iodine
(171 mg, 0.675 mmol) were sequentially added to a solution of
benzazepinium 5b in THF (15 mL, 96 mg, 0.15 mmol; À808C). The
reaction mixture was allowed to warm to À308C, and the solvents
were removed under reduced pressure. The residue was redis-
solved in methanol (15 mL) at room temperature, and sodium cya-
noborohydride (75 mg, 1.2 mmol) was added to the reaction mix-
ture, which was stirred for 1 h. Removal of the solvents under re-
duced pressure and purification by column chromatography on
silica gel (hexane/ethyl acetate 10:1) led to the isolation of benza-
zepine 9b (29 mg, 45%).
Experimental data for 2-butyl-3-cyclopropyl-5-phenyl-2,3-dihy-
dro-1H-benzo[c]azepine (7a) as a model compound: Yellowish
oil, yield=84%, Rf =0.23 (hexane/ethyl acetate 1:1). 1H NMR
(400 MHz, CDCl3, 258C, TMS): d=7.40–7.21 (m, 8H), 7.10 (m, 1H),
6.42 (d, J(H,H)=6.3 Hz, 1H), 3.76 (s, 2H), 2.88 (m, 1H), 2.59 (m, 1H),
1.87 (m, 1H), 1.65 (m, 2H), 1.41 (m, 2H), 1.05 (m, 1H), 0.99 (t,
J(H,H)=7.3 Hz, 3H), 0.65 (m, 1H), 0.57 (m, 1H), 0.25 (m, 1H),
0.10 ppm (m, 1H); 13C NMR (100 MHz, CDCl3, 258C): d=143.5 (C),
143.3 (C), 140.5 (C), 137.6 (C), 131.2 (CH), 129.9 (CH), 128.9 (CH),
128.5 (CH), 128.2 (CH), 127.6 (CH), 127.3 (CH), 127.1 (CH), 65.2 (CH),
54.2 (CH2), 50.8 (CH2), 30.2 (CH2), 20.9 (CH2), 15.0 (CH), 14.8 (CH3),
6.1 (CH2), 2.2 pm (CH2); HRMS (EI) calcd for C23H27N [M]: 317.2144;
found: 317.2145.
General experimental procedure for the preparation of 2,3-dihy-
dro-1H-2-benzo[c]azepines 8a–c: Trifluoromethanesulfonic acid
(27 mL, 0.3 mmol) was added followed by the corresponding mag-
nesium bromide (1.25 mmol; commercial solution) to a solution of
benzazepinium 5b (160 mg, 0.25 mmol) in THF (10 mL) at 208C.
After stirring the reaction mixture for 5 min, the solvents were re-
moved in vacuo and the residue purified by chromatography on
silica gel to obtain 2,3-dihydro-1H-2-benzo[c]azepines 8a–c as
single diastereoisomers.
2-Butyl-3-isopropyl-5-phenyl-4-(1-piperidinecarbonyl)-2,3-dihy-
dro-1H-benzo[c]azepine (9b): Colorless oil, yield=45%, Rf =0.19
1
(hexane/ethyl acetate 10:1). H NMR (300 MHz, CDCl3, 258C, TMS):
d=7.45–7.15 (m, 8H), 6.82 (d, J(H,H)=7.6 Hz, 1H), 3.79 (d, J(H,H)=
10.5 Hz, 1H), 3.54 (d, J(H,H)=10.5 Hz, 1H), 3.50–3.30 (m, 3H), 3.02–
2.90 (m, 3H), 2.75–2.55 (m, 2H), 1.80–1.05 (m, 8H), 0.95 (t, J(H,H)=
7.3 Hz, 3H), 0.84 (t, J(H,H)=7.6 Hz, 3H), 0.82 (d, J(H,H)=7.6 Hz,
3H), 0.76–0.58 (m, 1H), 0.57–0.40 ppm (m, 1H); 13C NMR (75 MHz,
CDCl3, 258C): d=171.3 (C), 141.8 (C), 140.8 (C), 140.6 (C), 138.6 (C),
133.4 (C), 130.3 (CH), 129.1 (CH), 129.0 (CH), 128.2 (CH), 128.1 (CH),
128.0 (CH), 127.4 (CH), 71.4 (CH), 59.0 (CH2), 56.6 (CH2), 47.4 (CH2),
42.2 (CH2), 31.8 (CH), 30.4 (CH2), 25.2 (CH2), 24.9 (CH2), 24.2 (CH2),
21.4 (CH3), 20.5 (CH2), 19.9 (CH3), 14.1 ppm (CH3); HRMS (EI) calcd
for C26H31N2O [MÀC3H7 +H]: 387.2436; found: 387.2439.
Experimental procedure for the preparation of 4-hydroxycar-
bonyl-2,3-dihydro-1H-2-benzo[c]azepine 9c: Iodine (57 mg,
0.225 mmol) was added to a solution of benzazepinium 5b in THF
(15 mL, 96 mg, 0.15 mmol; À808C), and the reaction mixture was
allowed to warm. When the mixture reached À608C, l-selectride in
THF (0.525 mL, 1m, 0.525 mmol) was added and allowed to warm
to 08C. Finally, the solvents were removed under vacuum and the
Experimental data for trans-2-butyl-1,5-diphenyl-3-isopropyl-
2,3-dihydro-1H-benzo[c]azepine (8a) as a model compound: Yel-
lowish oil, yield=74%, Rf =0.37 (hexane/ethyl acetate 40:1).
1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.53 (d, J(H,H)=7.1 Hz,
2H), 7.48–7.30 (m, 8H), 7.21–6.99 (m, 3H), 6.71 (d, J(H,H)=7.4 Hz,
1H), 6.35 (d, J(H,H)=6.6 Hz, 1H), 4.95 (s, 1H), 2.95 (m, 1H), 2.50 (m,
1H), 2.36 (m, 1H), 1.99 (m, 1H), 1.59 (m, 1H), 1.40–0.85 (m, 3H),
1.07 (d, J(H,H)=6.5 Hz, 3H), 0.98 (d, J(H,H)=6.5 Hz, 3H), 0.77 ppm
(t, J(H,H)=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=142.9
(C), 142.8 (C), 142.6 (C), 140.9 (C), 140.4 (C), 133.7 (CH), 129.4 (CH),
128.8 (CH), 128.7 (CH), 128.7 (CH), 128.2 (CH), 128.0 (CH), 127.2
(CH), 126.8 (CH), 126.7 (CH), 126.1 (CH), 67.1 (CH), 65.9 (CH), 49.3
(CH2), 31.2 (CH), 30.9 (CH2), 21.0 (CH2), 20.9 (CH3), 20.6 (CH3),
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residue was purified by column chromatography on silica gel
(hexane/ethyl acetate 3:1) to yield benzazepine 9c (44 mg, 83%).
2-Butyl-4-hydroxymethyl-3-isopropyl-5-phenyl-2,3-dihydro-1H-
benzo[c]azepine (9c): Pale-yellow oil, yield=83%, Rf =0.45
(hexane/ethyl acetate 3:1). 1H NMR (300 MHz, CDCl3, 258C, TMS):
d=7.45–7.10 (m, 8H), 6.72 (dd, J(H,H)=7.5 and 1.5 Hz, 1H), 4.24
(d, J(H,H)=12.1 Hz, 1H), 4.11 (d, J(H,H)=12.1 Hz, 1H), 3.70 (d,
J(H,H)=10.3 Hz, 1H), 3.38 (d, J(H,H)=10.3 Hz, 1H), 2.93 (d, J(H,H)=
9.6 Hz, 1H), 2.75 (m, 2H), 1.62 (m, 3H), 1.42 (m, 3H), 0.98 (t,
J(H,H)=7.3 Hz, 3H), 0.87 (d, J(H,H)=5.9 Hz, 3H), 0.69 ppm (m, 4H);
13C NMR (75 MHz, CDCl3, 258C): d=143.1 (C), 141.6 (C), 141.8 (C),
138.8 (C), 138.2 (C), 130.6 (CH), 129.4 (CH), 128.7 (CH), 128.6 (CH),
127.8 (CH), 127.7 (CH), 127.4 (CH), 71.1 (CH), 66.8 (CH2), 59.3 (CH2),
56.8 (CH2), 32.4 (CH), 31.4 (CH2), 21.5 (CH3), 23.9 (CH2), 20.8 (CH3),
14.6 ppm (CH3); HRMS (EI) calcd for C21H24NO [MÀC3H7 +H]:
306.1858; found: 306.1848.
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[9] The low overall yield for 5g (29%) can be partially explained because
approximately 30% of the corresponding Fischer carbene complex
1 was recovered.
All the calculations were carried out in the framework of density
functional theory (DFT) by using the M06 functional[22] as imple-
mented in the Gaussian 09 program package.[23] For the C, O, N,
and H atoms, the standard split-valence 6–31G* basis set[24] was
employed. For the tungsten atom, the Hay–Wadt effective core po-
tential[25] was used with the minimal basis-set split to [441/2111/
21]. Solvation was taken in account by using the SMD model[26]
with THF as the solvent (e=7.4257). All the geometry optimiza-
tions were carried out in solution with no restrictions. All the
points were characterized by vibrational-frequency calculations to
check the stationary points and characterized them as minima
(without imaginary frequencies) or transition states (with one
imaginary frequency). Further, the connectivity of the transition
states was confirmed by relaxing the transition-state geometry
toward the reactant and product. Gibbs-energy corrections at
298.15 K and 105 Pa pressure were computed, including zero-point
energy corrections. All the reported energies herein correspond to
Gibbs energies in solution, obtained from potential energies (in-
cluding solvation) and Gibbs-energy corrections.
[10] CCDC-959023 (5a) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
[11] A similar structure to 5a (R1 =Ph; R2 =c-C3H5) was obtained by starting
from the analogous chromium compound.
[12] For tungsten equivalents, a [4+2] heterocycloaddition was observed: J.
Barluenga, M. Tomꢀs, J. A. Lꢁpez-Pelegrꢂn, E. Rubio, Tetrahedron Lett.
1997, 38, 3981–3984.
Acknowledgements
[13] a) J. Barluenga, M. Tomꢀs, E. Rubio, J. A. Lꢁpez-Pelegrꢂn, S. Garcꢂa-
Granda, P. Pertierra, J. Am. Chem. Soc. 1996, 118, 695–696; b) J. Barluen-
ga, M. Tomꢀs, E. Rubio, J. A. Lꢁpez-Pelegrꢂn, S. Garcꢂa-Granda, M. PØrez
Priede, J. Am. Chem. Soc. 1999, 121, 3065–3071; for a photochemical
example of this type of cyclization with imines and tungsten com-
plexes, see: c) M. Blanco-Lomas, A. Caballero, P. J. Campos, H. F. Gon-
zꢀlez, S. Lꢁpez-Sola, L. Rivado-Casas, M. A. Rodrꢂguez, D. Sampedro, Or-
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[14] With alkenyl Fischer carbenes: a) J. Barluenga, M. Tomꢀs, A. Ballesteros,
J. Santamarꢂa, F. Lꢁpez-Ortiz, J. Chem. Soc. Chem. Commun. 1994, 321–
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jo, F. Lꢁpez-Ortiz, S. Garcꢂa-Granda, P. Pertierra, Chem. Eur. J. 1996, 2,
88–97; for interesting catalytic [4+3]-heterocycloaddition reactions
with 1-azadienes, see: with rhodium: c) M. P. Doyle, W. Hu, D. J. Tim-
mons, Org. Lett. 2001, 3, 3741–3744; with gold: d) N. D. Shapiro, F. D.
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W. Hu, J. Org. Chem. 2012, 77, 5184–5190.
This research was partially supported by the Spain and Princi-
pado de Asturias Governments (CTQ2010-20517-C02-01,
CTQ2011-24800 and FC-11CO11-17) and Fondos Europeos para
el Desarrollo Regional (FEDER). A.R. thanks Ministerio de Educa-
ciꢁn and European Union (Fondo Social Europeo) for a predoc-
toral fellowship. We are also grateful to Dr. A. L. Suꢀrez-Sobrino
(Universidad de Oviedo) for his assistance with the X-ray stud-
ies, the Supercomputing Center of Galicia (CESGA) for CPU
time allocation, and Prof. J. Barluenga and Prof. M. Tomꢀs (Uni-
versidad de Oviedo) for helpful discussions.
Keywords: alkynes
· carbenes · heterocycles · imines ·
regioselectivity
[15] Ring closure to seven-membered rings involving a [1,2]-{W(CO)5} shift is
well documented: a) J. Barluenga, S. Martꢂnez, A. L. Suꢀrez-Sobrino, M.
Tomꢀs, J. Am. Chem. Soc. 2002, 124, 5948–5949; b) J. Barluenga, P.
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Received: January 23, 2014
Published online on && &&, 0000
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FULL PAPER
&
Heterocycles
J. Gonzꢀlez, A. Gꢁmez, I. Funes-Ardoiz,
J. Santamarꢂa,* D. Sampedro
&& – &&
Intermolecular and Regioselective
Access to Polysubstituted Benzo- and
Dihydrobenzo[c]azepine Derivatives:
Modulating the Reactivity of Group 6
Non-Heteroatom-Stabilized Alkynyl
Carbene Complexes
Choose your substitution pattern:
Non-heteroatom-stabilized tungsten–
carbene complexes synthesized in situ
have been used in a modular approach
to provide access to 2-benzazepinium
isolable intermediates as a starting
point to fully substituted 2-benzazepine
derivatives (see figure). These intermedi-
ates were obtained under very mild
conditions from simple compounds,
such as acetylides, Fischer-type alkoxy-
carbenes, and phenylimines. An acety-
lide substitution pattern controls the re-
action.
Chem. Eur. J. 2014, 20, 1 – 9
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These are not the final page numbers! ÞÞ