A Ring Expansion Route to Benzofused N-Heterocycles Through Aryne Insertion into 1,3-Diaza-heterocycles

Article abstract of DOI:10.1002/ejoc.201900570

Arynes have been found to undergo formal σ-bond insertion into a C(sp3)–N bond for the first time. This transformation is utilized in the ring expansion of 1,3-diaza-heterocycles to afford benzofused medium-ring N-heterocycles in a single step. This represents a novel route to biologically relevant 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine?s, prepared directly from easily accessible imidazolidines. An example of the ring expansion of a 1,3-diazetidine is also reported, which affords the corresponding 1,2,3,4-tetrahydroquinazoline.

Full text of DOI:10.1002/ejoc.201900570

A Journal of
Accepted Article
Title: A Ring Expansion Route to Benzofused N-Heterocycles via
Aryne Insertion into 1,3-Diaza-heterocycles
Authors: Yun Yang, Yue Xu, and Christopher Raymond Jones
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10.1002/ejoc.201900570
European Journal of Organic Chemistry
COMMUNICATION
A Ring Expansion Route to Benzofused N-Heterocycles via Aryne
Insertion into 1,3-Diaza-heterocycles
Yun Yang,[a] Yue Xu,[a] and Christopher R. Jones*[a]
Abstract: Arynes have been found to undergo formal σ-bond
insertion into a C(sp3)-N bond for the first time. This transformation
is utilized in the ring expansion of 1,3-diaza-heterocycles to afford
anticonvulsants,13 platelet-activating factor antagonists,14 human
immunodeficiency virus (HIV) transactivator Tat antagonists15
and reverse transcriptase inhibitors.16
benzofused medium-ring N-heterocycles in
a single step. This
represents a novel route to biologically relevant 2,3,4,5-tetrahydro-
1H-benzo[e][1,4]diazepines, prepared directly from easily accessible
imidazolidines. An example of the ring expansion of a 1,3-diazetidine
is also reported, which affords the corresponding 1,2,3,4-
tetrahydroquinazoline.
A) C(sp2)-N σ-bond insertion: ureas6 & amides7
R1
HN
Z
O
R1
Z
R
N
R
H
R
= NR2, Ar, Alk
H
1
4
O
Introduction
1 H
N
R
1 N
R
R
Z
Arynes are versatile reactive intermediates that facilitate the
rapid generation of molecular complexity.1 The advent of aryne
precursors that act under mild conditions, such as o-silylaryl
triflates2 and the hexadehydro-Diels-Alder (HDDA) reaction of
polyalkynyl substrates,1j,3 has led to a recent resurgence in the
development of novel reactivity. One particularly valuable area
of aryne chemistry is the formal insertion of the arene motif into
a wide range of σ- and π-bonds, including carbon-carbon,
carbon-heteroatom and heteroatom-heteroatom bonds.4 The
transformations typically occur under mild conditions without the
need for additional Lewis acid or transition metal reagents and
generate useful poly-functionalized aromatic products.5 For
example, biologically active heterocycles and o-functionalized
aniline derivatives – key building blocks for synthesis – have
been accessed via aryne insertion into the C(sp2)-N bond of
ureas,6 amides7 and imides7b,8 (Scheme 1A).9 These
transformations are understood to proceed via initial N-arylation
R
Z
O
O
2
3
B) C(sp3)-N σ-bond insertion: 1,3-diaza-heterocycles - this work
R1
R1
N
Z
R
N
R2
N
Z
n = 0,1
n = 0,1
N
R
ring expansion
R2
5
8
N
N
R1
7
R1
R2
R2
N
N
6
Scheme 1. Aryne insertion into C-N σ-bonds.
of 1, affording zwitterion
2 that undergoes subsequent
intramolecular nucleophilic substitution at the carbonyl carbon,
via azetidinium 3, to furnish the insertion products 4.
Existing methods to synthesize 1,4-benzodiazepines are
typically multistep processes.17 These include cyclization of o-
18
Given our interests in the development of new aryne-
based methodology,10 we envisaged a related approach to the
synthesis of biologically relevant N-heterocycles via the formal
insertion of an aryne into a C(sp3)-N σ-bond of 1,3-diaza-
heterocycles 5 (Scheme 1B). It was proposed that N-arylation
would generate zwitterionic intermediate 6, which should be in
equilibrium11 with the ring-opened form 7 that could undergo
intramolecular cyclization to reveal the ring-expanded
benzofused N-heterocycle 8. For example, employing readily
accessible 1,3-imidazolidines (5, n = 1) would reveal a new route
to biologically active 1,4-benzodiazepines (8, n = 1), one of the
most widely used heterocycles in medicinal chemistry.12 These
halobenzoic acid derivatives with 1,2-ethylenediamines,
o-
o-
amino-methylanilines
with
bis-electrophiles,19
aminobenzophenones with α-amino acid derivatives20 and the
Pictet-Spengler reaction of N-phenyl-1,2-ethylenediamines.21
Herein we report the development of a new direct route to the
synthesis
of
2,3,4,5-tetrahydrobenzo-1,4-diazepines
that
operates via a ring expansion of readily accessible 1,3-diaza-
heterocycles. This approach showcases the first examples of a
formal aryne insertion into a C(sp3)-N σ-bond.
Results and Discussion
privileged
scaffolds
are
employed
as
sedatives,
In order to test our hypothesis of a formal insertion of benzyne
into an aminal C-N σ-bond, 1,3-diphenylimidazolidine 9 was
exposed to 2-trimethylsilylphenyl triflate 10a under a variety of
aryne-forming conditions (see Table 1 for selected optimization
studies).22 Pleasingly, initial attempts using CsF in acetontrile
[a]
Y. Yang, Y. Xu, Dr C. R. Jones
School of Biological and Chemical Sciences,
Queen Mary University of London,
Mile End Road, London, E1 4NS, UK.
E-mail: c.jones@qmul.ac.uk
furnished
the
C-N
insertion
product,
2,3,4,5-
Homepage: https://www.qmul.ac.uk/sbcs/staff/christopherjones
tetrahydrobenzodiazepine 11a, as the major product in good
yield after 4 hours (entry 1). Interestingly, mono-arylated linear
1,2-ethylenediamine 12 and the bis-arylated analogue 13 were
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900570
European Journal of Organic Chemistry
COMMUNICATION
also identified; both by-products involving ring-opening of the
imidazolidine ring and loss of the C-2 methylene group.
Evaluation of a range of common activators for o-silylaryl triflate
precursors identified CsF as the most promising reagent (entries
1-7) and revealed that the precise distribution between the ring-
expanded (11a) and ring-opened (12 and 13) products was
extremely dependent upon the reaction conditions.23 Increasing
the temperature to 80 ˚C led to more by-product formation (entry
8), whereas mainly unreacted imidazolidine 9 was recovered
when the temperature was lowered to 30 ˚C (entry 9). A small
increase in benzyne precursor (1.2 equivalents) resulted in more
bis- arylated diamine 13 (entry 10). Optimal concentration was
found to be 0.1 M, as both higher and lower dilutions caused a
drop in the insertion:linear product ratios (entry 1 vs entries 11
and 12). Considering the proposed mechanism for C-N insertion
(see Scheme 1B), it followed that undesired protonation of the
intermediate aryl anion (6 or 7) would prohibit cyclization to the
benzodiazepine and instead favour ring-opening and
hydrolysis.24 As such, attempts were made to remove trace
water (4 Å molecular sieves, entry 13) as well as changing from
acetonitrile to ethereal solvents10c (DME, entry 14; THF, entries
3 and 6); however, all changes resulted in less C-N insertion.
Finally, the addition of transition metal salts such as CuI and AgI
(entries 15 and 16) – proposed to stabilize the aryl anion25 and
thereby favour cyclization – did not improve the reaction. In the
case of CuI this led to a significant reduction in conversion,
potentially caused by the imidazolidine binding to the Cu.
With optimized conditions in hand for the formal insertion
of benzyne into a C(sp3)-N bond of 1,3-diphenylimidazolidine 9
(entry 1, Table 1), we began to explore the scope of the ring
expansion reaction. Pleasingly, tetrahydrobenzodiazepines 11a-
h were furnished in moderate to good yields when N,N-
diphenylimidazolidine 9 was exposed to a range of substituted
aryne precursors 10a-h (Scheme 2). It is noteworthy that longer
reaction times were required for arynes 10b-h (16 h) in
comparison to benzyne 10a (4 h), although identical results were
achieved when 10a was also left for 16 h. The transformation
was equally tolerant of arynes substituted with electron-donating
(methylenedioxy, 10b, 3,4-dimethyl, 10c, cyclopentyl, 10e, 3-
methoxy, 10f, 5-methyl, 10h) or electron-withdrawing groups
(3,4-difluoro, 10d, 5-fluoro, 10g). Interestingly, benzodiazepines
bearing alkyl or fluoro substituents (10c-e and 10g-h) were
found to be unstable to purification by flash column
chromatography. As a result, the crude reaction mixtures were
treated with trifluoromethanesulfonic acid (TfOH) to generate the
corresponding triflate salts, which subsequently proved
amenable to chromatographic purification. Treatment of
imidazolidine 9 with unsymmetrical arynes led to regioisomeric
mixtures of the corresponding benzodiazepine products. The 3-
methoxy aryne derivative 10f gave a 3:1 mixture of the 6- and 9-
methoxy-1,2,3,4-tetrahydrobenzodiazepines 11f. Similarly, the
5-fluoro derivative 10g afforded a 3:1 preference for the 7-fluoro
product. Finally, the less polarized 5-methyl-substituted aryne
led to a 1:1 regioisomeric mixture of 11h. These observations
are consistent with initial nucleophilic attack of nitrogen at the
distal site of the aryne, resulting in an aryl anion that is stabilized
by the adjacent electron-withdrawing substituent.
Table 1. Selected optimization studies for benzyne insertion into N,N-diphenyl
imidazolidine 9.
TMS
Ph
N
Ph
Ph
OTf
10a
(1.0 equiv.)
Ph
Ph
N
H
Ph
12
13
N
Ph
Ph
N
N
+
N Ph
activator, 4 h
solvent [0.1 M]
temperature
N
N
9
Ph
Ph
11a
Entry
Activatora
Additiveb
Solvent
T (˚C)
Yieldc (%)
9
11 12 13
1
2
CsF
CsF
TBAFd
TBAT
KF
–
CH3CN
CH3CN
THF
50
50
50
50
50
50
50
80
30
50
50
50
50
50
50
50
5
55 25 10
18-c-6
12 45 18 15
3
–
5
7
5
5
65 10
67
The reaction was found to be amenable to different N-
substituted imidazolidines, as both electron-withdrawing (Boc,
14; CO2Me, 15) and electron-donating groups (Me, 16) provided
tetrahydrobenzodiazepines 24-26 in low to moderate yields over
16 hours (Scheme 3).26 Symmetrical 1,3-dimethylimidazolidine
20 proved to be too electron-rich, affording solely the linear 1,2-
4
–
CH3CN
CH3CN
THF
7
5
18-c-6
29 10 10 35
22 42 26
6
KF
18-c-6
9
7
Cs2CO3
CsF
18-c-6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CNf
CH3CNg
CH3CN
DME
10 26 47 10
12 25 40 16
8
–
ethylenediamine products; the same outcome as when
a
9
CsF
–
–
60 20
5
0
substituent was introduced at C-2 of the imidazolidine ring (21).
Conversely, the electron-poor 1,3-di-Boc-imidazolidine 22 and
1,3-diphenylbenzimidazolidine 23 led to complete recovery of
10e
11
12
13
14h
15
16
CsF
5
50 20 15
CsF
–
20 42 30
10 34 39
9
8
starting material. However, switching to
a more electron-
CsF
–
donating para-methoxy phenyl (PMP) group on nitrogen (17) led
to the corresponding dibenzodiazepine 27 in moderate yield.
Finally, preliminary studies revealed that aryne insertion is not
limited to imidazolidine derivatives. For example, treating 1,3-
diphenyl-1,3-diazetidine 18 with benzyne precursor 10a at 35 ˚C
led to the corresponding 1,2,3,4-tetrahydroquinazoline 28.
Furthermore, linear N,N'-dimethyl-N,N'-diphenylmethanediamine
19 also underwent formal aryne insertion, affording the
aminomethylaniline 29 in low yield.
CsF
4Å MS
6
25 40 15
CsF
–
70
8
10
4
3
4
CsF
CuIi
AgIi
CH3CN
CH3CN
52 27 18
16 50 23
CsF
[a]
3 equiv. activator. [b] 3
equiv. additive. [c] 1H NMR yield vs
dibromomethane internal standard. [d] 1.0 M in THF. [e] 1.2 equiv. benzyne
10a and 3.6 equiv. CsF. [f] 0.01 M. [g] 0.5 M. [h] reaction left for 24 h until
all benzyne 10a consumed. [i] 0.2 equiv additive. TBAT
=
A
mechanism
for
the
formation
of
tetrabutylammonium triphenyldifluorosilicate. MS = molecular sieve.
tetrahydrobenzodiazepines and the observed by-products is
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10.1002/ejoc.201900570
European Journal of Organic Chemistry
COMMUNICATION
R1
N
R
TMS
TMS
OTf
Ph
10a-h
(1 equiv.)
R1
10a
(1 equiv.)
R
N
Ph
N
R2
N
OTf
N
N Ph
R
n
n
N
N
R
CsF (3 equiv.)
MeCN, 16 h, 50 ºC
CsF (3 equiv.)
MeCN, 16 h, 50 ºC
R2
Ph
9
11a-h
14-19
24-29
producta
producta
aryne
1,3-diamine
Ph
N
Ph
N
TMS
Ph
N
N Boc
OTf
N
N
Ph
Boc
11a, 55% (45%)b
10a
14
24, 40% (20%)
Ph
N
Ph
N
TMS
O
O
Ph
N
N CO2Me
O
OTf
O
N
N
Ph
CO2Me
10b
10c
11b, 55% (42%)
15
25, 10% (6%)
Ph
Me
N
Me
Me
TMS
OTf
N
Me
Me
Me
N
N
N Boc
16
N
N
Ph
11c, 55% (37%)c
Boc
26, 50% (34%)
Ph
F
F
TMS
OTf
PMP
N
N
F
F
PMP
N PMP
N
Ph
10dd
N
11d, 40% (35%)c
PMP
Ph
N
17
27, 40% (30%)
TMS
OTf
Ph
N
Ph
N
N
N
N
Ph
Ph
10e
OMe
Ph
11e, 43% (40%)c
18
28, 15% (11%)b
Ph
N
Ph
TMS
Ph
Ph
NMe
Me
N
N
N
MeO
Me Me
N
OTf
10f
Ph
Ph
11f, 47% (40%)
19
29, 28% (10%)c
6- / 9-OMe = 3:1e
Unsuccessful substrates:
Me
Ph
N
Ph
N
Me
Boc
TMS
N Ph
Ph
N
N
N
N Me
N Boc
F
N Ph
F
OTf
10gd
N
Ph
20
21
22
23
11g, 50% (30%)c
7- / 8-F = 3:1e
linear 1,2-diamine products
recovered starting material
Scheme 3. Scope of C-N insertion with different imidazolidine derivatives. a 1H
NMR yield vs dibromomethane internal standard, isolated yields in
parentheses. b 35 ˚C. c 4 h. PMP = para-methoxyphenyl.
Ph
N
TMS
OTf
Me
Me
N
Ph
10h
11h, 45% (30%)c
proposed in Scheme 4. Initial nucleophilic attack of nitrogen onto
the aryne affords zwitterion 30 that is in equilibrium with the ring-
opened form 31. A 7-endo-trig cyclization of 31 furnishes 11a
and completes the formal insertion reaction. However, in the
presence of trace water, deleterious protonation of either 30 or
31, followed by hydrolysis, results in loss of the C-2 methylene
7- / 8-Me = 1:1e
a
Scheme 2. Scope of C-N insertion with different aryne derivatives. 1H NMR
b
yield vs dibromomethane internal standard, isolated yields in parentheses.
h. Isolated as HOTf salt. 1.5 equiv. aryne precursor. ratio determined by
analysis of 1H NMR spectrum of crude mixture.
4
c
d
e
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10.1002/ejoc.201900570
European Journal of Organic Chemistry
COMMUNICATION
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Further arylation with another equivalent of aryne leads to 13.
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Ph
N
N
Ph
N
N
Ph
31
Ph
30
N
Ph
N
Ph
9
cyclization
(7-endo-trig)
H2O
[5]
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Ph
N
Ph
N
Ph
N
Ph
Ph
Ph
H
N
N
N
Ph
Ph
Ph
13
12
11a
[6]
[7]
[8]
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Insertion into C(sp)-N bond of aryl cyanamides: B. Rao, X. Zeng, Org.
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scaffolds, accessed via
a
number of tetrahydro-1,4-benzodiazepine
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a
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ethylenediamine by-products proved
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insertion products obtained. Encouraging preliminary
a challenge for the
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insertion and investigations are currently underway to evaluate
the general applicability of this approach.
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Acknowledgments
We are grateful to the EPSRC (EP/M026221/1, C.R.J.) and the
China Scholarship Council (Y.Y.) for financial support. We also
thank the EPSRC UK National Mass Spectrometry Facility at
Swansea University.
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Keywords: arynes • N-heterocycles • insertion • ring expansion
• tetrahydro-1,4-benzodiazepine
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Chem. 2017, 14, 453 and references therein.
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10.1002/ejoc.201900570
European Journal of Organic Chemistry
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[22] M. K. Denk, S. Gupta, J. Brownie, S. Tajammul and A. J. Lough, Chem.
Eur. J. 2001, 7, 20; see SI for full details of starting material synthesis.
[23] Use of alternative aryne precursors such as benzenediazonium-2-
carboxylate resulted in significant recovery of starting material and
similar product distribution.
[25] C. Xie, L. Liu, Y. Zhang, P. Xu, Org. Lett. 2008, 10, 2393.
[26] Products 24-29 underwent partial decomposition upon chromatographic
purification with different stationary phases. Formation of the
corresponding triflate salts did not improve isolated yields.
[24] Addition of small quantity of D2O led to decrease in insertion product
and deuterium incorporation into by-products, see SI for full details.
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