Calcium-Catalyzed Synthesis of 1,2-Disubstituted 3-Benzazepines

Article abstract of DOI:10.1002/ejoc.201501106

A short and highly stereoselective chiral pool synthesis of tetrahydro-3-benzazepines as potential drug molecules is described, using simple enantiopure amino acids as the chiral building blocks. Intramolecular Friedel-Crafts alkylation towards seven-membered rings was achieved with high diastereoselectivity for the first time and accomplished by a biocompatible calcium catalyst. The simple and cost efficient approach allows for the variation of all substituents in the 3-benzazepine by a change of the substitution pattern in one or more of the reagents, while leaving the general synthetic route unchanged. Furthermore, assignment of the absolute configuration of the 3-benzazepine derivative is straightforward, based on the amino acid building block employed. A new stereoselective chiral pool synthesis of 1,2-disubstituted 3-benzazepines was developed, using enantiopure amino acids as chiral building blocks. The key step is based on the first diastereoselective Friedel-Crafts cyclization towards this pharmacologically highly interesting compound class and accomplished by a biocompatible calcium catalyst. The modular concept allows for variation of all substituents, leaving the general synthetic route unchanged.

Full text of DOI:10.1002/ejoc.201501106

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201501106
Calcium-Catalyzed Synthesis of 1,2-Disubstituted 3-Benzazepines
Helena Damsen[a] and Meike Niggemann*[a]
Keywords: Calcium / Benzazepines / Friedel–Crafts / Cyclization / Chiral pool
A short and highly stereoselective chiral pool synthesis of
tetrahydro-3-benzazepines as potential drug molecules is de-
scribed, using simple enantiopure amino acids as the chiral
building blocks. Intramolecular Friedel–Crafts alkylation
towards seven-membered rings was achieved with high dia-
stereoselectivity for the first time and accomplished by a
biocompatible calcium catalyst. The simple and cost efficient
approach allows for the variation of all substituents in the 3-
benzazepine by a change of the substitution pattern in one
or more of the reagents, while leaving the general synthetic
route unchanged. Furthermore, assignment of the absolute
configuration of the 3-benzazepine derivative is straightfor-
ward, based on the amino acid building block employed.
catalyst system, which allows the selective alkylation of ar-
enes using benzylic, allylic, and propargylic alcohols.[10]
Moreover, model studies towards the diastereoselective alk-
ylation of chiral α-benzylic carbocations (unpublished) en-
couraged us to elaborate a new stereoselective strategy for
the synthesis of differently substituted tetrahydro-3-benz-
azepines by using a calcium-catalyzed intramolecular Frie-
del–Crafts reaction as the key step. The straightforward and
highly modular strategy towards the cyclization precursors
2, shown in Scheme 1, is based upon the linkage of three
readily available building blocks through classical synthetic
operations. Simple enantiopure amino acids 3, provide the
stereochemical information. They are coupled to the arene
building block by reductive amination, followed by treat-
ment with an organometallic reagent for the incorporation
of the R2-moiety. Thereby, every single substituent in the
lead molecule can be varied by a simple change of the sub-
stitution pattern in one or more reagents, leaving the gene-
ral synthetic route unchanged. This is a very cost effective
strategy, which, in addition, allows for a straightforward as-
signment of the absolute stereochemistry in the final drug
molecule, based on the configuration of the amino acid.
Introduction
N-Heterocycles containing a phenylethylamine substruc-
ture are found in many natural products and biologically
active molecules.[1] A class of compounds that contain such
a structural subunit are the tetrahydro-3-benzazepines,
which play a vital role in treatments of neurodegenerative
diseases such as Alzheimer’s or Parkinson’s disease, due to
their structural analogy to the corresponding neurotrans-
mitters.[2] As a consequence of these interesting biological
properties, derivatives of the 3-benzazepines have been syn-
thesized and evaluated pharmacologically in the past. For
example, strategies for the preparation of 3-benzazepine
compounds have been developed based on transition-metal-
mediated cyclizations,[3] such as the Heck reaction,[4] using
expensive and highly toxic transition-metal catalysts unsuit-
able for large-scale applications. A transition-metal-free al-
ternative is an acid-mediated Friedel–Crafts cyclization[5]
using a large excess of acid, traditionally as the solvent.
Unfortunately, these SN1 processes suffer from poor dia-
stereoselectivity, generally in the range of 1:1[6] to 3:1,[7]
thereby precluding the formation of enantiopure 3-benz-
azepines through operationally simple chiral pool synthesis.
First diastereoselective transformations proceeding by an
SN1 mechanism, were published only recently.[8]
Therefore, stereoselective approaches have focused so far
on ring enlargements, such as the Stevens rearrangement,
as good diastereoselectivities were achieved by these meth-
ods.[6b,9]
Our group has recently developed an efficient Friedel–
Crafts alkylation reaction based on a Ca(NTf2)2/Bu4NPF6
Scheme 1. Diastereoselective chiral pool synthesis of 3-benzazep-
ines 1.
[a] RWTH Aachen University, Institute of Organic Chemistry
Landoltweg 1, 52074 Aachen, Germany
Results and Discussion
With these considerations in mind we set out to synthe-
size a small series of tetrahydro-3-benzazepines as a proof
E-mail: niggemann@oc.rwth-aachen.de
http://www.oc.rwth-aachen.de/akniggemann/Main2.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201501106.
7880
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Eur. J. Org. Chem. 2015, 7880–7883

Calcium-Catalyzed Synthesis of 1,2-Disubstituted 3-Benzazepines
of concept. The synthesis of the cyclization precursor 2 All products 6a–6e were obtained as mixtures of dia-
starts from commercially available alcohol 4, which was oxi- stereomers. As the newly formed stereocenter will be erased
dized and subjected to reductive amination with the respec- and reset in the subsequent cyclization step, no further at-
tive amino acid methyl ester hydrochloride 3a–3c under tention was required and diastereomeric ratios remained
standard reaction conditions (Scheme 2). The resulting unanalyzed.
amines were protected to prevent difficulties in the subse-
With cyclization precursors 6a–6e in hand, the intramo-
quent organometallic reaction as well as the calcium-cata- lecular Friedel–Crafts reaction in the presence of our cal-
lyzed Friedel–Crafts cyclization. As initial attempts to use cium-based catalyst system consisting of Ca(NTf2)2 and
an N-tosyl group failed a later deprotection, a p-nitro- Bu4NPF6 was investigated (Table 2). The process was exam-
benzenesulfonyl (p-nosyl) group was selected, which can be ined with 6f as a model substrate. Even though conven-
easily removed (vide infra).
tional heating gave approximately the same results, we
opted for carrying out the reaction under microwave condi-
tions as this considerably shortened the reaction times.
Hence, after 15 min of microwave irradiation at 100 °C in
1,2-dichloroethane, the desired 3-benzazepine 7f was iso-
lated in an excellent yield of 95% (Table 2, entry 1). When
the reaction was performed at 70 °C, full conversion was
not achieved. Decreasing the amount of the calcium cata-
lyst to 5 mol-% considerably slowed down the conversion
of the starting material. Other solvents, such as toluene or
Scheme 2. Synthesis of α-chiral aldehydes 5a–5c: (i) CH2Cl2,
15 min, room temp.; (ii) MeOH, 12 h, room temp.; (iii) py, 3 h, dichloromethane, considerably decreased the reaction rate
room temp.; (iv) CH2Cl2, 2 h, –78 °C.
(Table 2, entry 2), whereas in MeNO2 the yield was only
slightly lower in comparison to 1,2-dichloroethane. The at-
Reduction with DIBAL in dichloromethane at –78 °C,
tempt to perform the cyclization at room temperature gave
followed by reoxidation in the case of 5c, provided alde-
only 23% yield of 3-benzazepine 7a after 3 days (Table 2,
hydes 5a and 5b. Initial attempts to add a simple Grignard
entry 3). Among other Lewis acids, the calcium catalyst
reagent to these aldehydes resulted in complex reaction mix-
clearly showed superior reactivity, as only in the presence of
tures. To discourage side reactions and to lower the risk for
Zn(OTf)2 or BF3·OEt2 a moderate yield of 7f was obtained
racemization of the stereocenter in the α-chiral aldehydes 5,
(Table 2, entries 4–12). Complete conversion was also not
the in situ formation of milder organometallic reagents by
achieved under Brønsted “super” acid catalysis (HNTF2,
transmetalation was envisaged. The addition of stoichio-
Table 2, entry 13).
metric amounts of either LiCl or ZnCl2 to PhMgCl in THF
gave again mixtures of undesired side products and only a
small amount of the desired product could be isolated.
Table 2. Optimization of the Ca2+-catalyzed Friedel–Crafts cycliza-
tion.
Also, a change of solvent, to Et2O did not improve the re-
sults. To our delight, the combination of one equivalent of
each, LiCl and ZnCl2 with 3 equiv. of PhMgCl dramatically
increased the yield of 6. Under these optimized reaction
conditions aldehydes 5a–5c were converted into the corre-
sponding cyclization precursors 6a–6c (Table 1). In ad-
dition, the reaction was performed exemplarily with two
further Grignard reagents yielding the alcohols 6d and 6e.
Entry[a] Catalyst
Bu4NPF6 [mol-%] Solvent
T [°C] Yield[c] [%]
Table 1. Addition of organometallic reagents to aldehyde 5.
1
2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Sc(OTf)3
AgOTf
10
10
10
10
10
10
10
10
10
10
10
10
10
DCE
toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
100
100
25
95
35
23
–
3[b]
4
100
100
100
100
100
100
100
100
100
100
5
–
–
–
–
6
7
8
Al(OTf)3
Al(OTf)3
InCl3
Entry[a] Amino acid R1
R2MgX
Product Yield [%][b]
9
Ga(OTf)3
Ga(OTf)3
Zn(OTf)2
BF3·OEt2
HNTf2
–
–
1
2
3
4
5
Phe
Ala
Tyr
Phe
Phe
Bn
Me
PhMgCl
PhMgCl
6a
6b
6c
6d
6e
68
63
61
50
68
10
11
12
13
74
67
75
PMB PhMgCl
Bn
Bn
4-MeOC6H4MgCl
4-ClC6H4MgCl
[a] Catalyst and Bu4NPF6 and Ca(NTf2)2 were added to amino
alcohol 6f (0.25 mmol) in 1 mL of solvent and stirred for 15 min
under microwave irradiation at 100 °C. [b] Reaction was stirred at
25 °C for 72 h. [c] Isolated yield.
[a] LiCl, ZnCl2 and Grignard reagent were stirred in THF at 0 °C
for 45 min. The solution was cooled to –78 °C and aldehyde 5 was
added. The mixture was stirred at –78 °C for 3 h. [b] Isolated yield.
Eur. J. Org. Chem. 2015, 7880–7883
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H. Damsen, M. Niggemann
SHORT COMMUNICATION
Using the optimized conditions the amino alcohols 6a–
6e were converted into the desired products7a–7e, giving
excellent yields of 91–96% (Figure 1). To showcase the ver-
satility of the calcium-catalyzed Friedel–Crafts cyclization
also for substrates with non-activated benzene rings model
compound 7g was included. Moreover, the reaction occurs
highly diastereoselectively despite the high reaction tem-
perature of 100 °C, yielding exclusively the trans-dia-
stereomer in all cases. The minor cis-diastereomer was not
detected by NMR spectroscopy or HPLC analysis. The
trans-configuration was unambiguously determined by
NOE experiments.
Figure 3. Proposed transition state for the diastereoselective SN1
reaction.
philic arene substituent. This leads to a larger proportion
of an SN2-like mechanism, resulting in net inversion of the
stereocenter at the hydroxyl moiety and thus poor dia-
stereoselectivity because the reaction is no longer governed
solely by steric factors. As mentioned above, the high effi-
ciency of the calcium catalyst ensures quantitative ioniza-
tion and thus, the SN2-like pathway does not interfere with
the ionic pathway. Hence, the stereochemical outcome of
the cyclization is exclusively determined by virtue of the
steric repulsion induced by the R1 substituent (the former
amino acid) which renders the two faces of the planar
carbocation 8 diastereotopic.
Figure 1. Results of the Ca2+-catalyzed diastereoselective cycliza-
tion.
After the successful synthesis of the 3-benzazepines, we
focused on further elaboration at the nitrogen atom. For
these derivatizations we chose once more 3-benzazepine 7a
as a model compound. The p-nosyl group was easily re-
moved in the presence of PhSH and K2CO3. Reductive
amination of the resulting amine 9a with formaldehyde pro-
vided 10a in 90% yield. Alkylation with benzyl bromide in
the presence of NaH yielded 3-benzazepine 11a (Scheme 3).
Therefore, the preferred conformation of 3-benzazepine
7a was assigned by DFT-based computational methods.
Figure 2 shows the observed NOE interactions for 3-benz-
azepine 7a, found between H-1 and H-2, as well as between
H-4 and one of the benzylic hydrogen atoms. Furthermore,
the value of the coupling constant (J1,2 = 5.4 Hz) was in
accordance with previously reported trans-1,2-disubstituted
3-benzazepines.[8,11]
Scheme 3. Derivatization of 3-benzazepine 7a.
Conclusions
We have developed a simple and efficient chiral pool syn-
thesis for the stereoselective formation of 1,2-disubstituted
tetrahydro-3-benzazepines. These compounds were ob-
tained through a Friedel–Crafts cyclization that was
achieved with high diastereoselectivity for the first time,
owing to the particular potency of the calcium catalyst used
for the ionization of the cyclization precursor. Evaluation
of the bioactivity of the newly synthesized compounds is
currently underway.
Figure 2. Preferred conformation of 7a and observed NOE signals.
The remarkable diastereoselectivity of the reaction can
be explained by the particular potency of the Lewis acidic
calcium catalyst, due to which the formation of the carbo-
cation 8 (Figure 3) is highly efficient and occurs quantita-
tively.
In previous studies, mostly in the presence of several
equivalents of strong Brønsted acids as ionization pro-
moters,[12] a low to moderate diastereoselectivity was ob-
served. This was explained by a cyclization that proceeds
only in part through an SN1 mechanism. The inefficient
ionization imparted by the acid requires the assistance of a
Experimental Section
General Procedure for the Diastereoselective Calcium-Catalyzed
pronounced neighboring group participation of the nucleo- Friedel–Crafts Cyclization: Bu4NPF6 (10 mol-%) and Ca(NTf2)2
7882
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Calcium-Catalyzed Synthesis of 1,2-Disubstituted 3-Benzazepines
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Received: August 26, 2015
Published Online: November 13, 2015
Eur. J. Org. Chem. 2015, 7880–7883
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7883