Regiocontrolled and Stereoselective Syntheses of Tetrahydrophthalazine Derivatives using Radical Cyclizations

Article abstract of DOI:10.1002/chem.201805249

Tetrahydrophthalazine derivatives have found important applications in pharmaceutical research, but existing synthetic methods are unable to access them regio- and stereoselectively. Here, a new approach is presented that addresses these challenges by utilizing a 6-endo-trig radical cyclization in the key step. The desired tetrahydrophthalazines can be accessed in high yields (55–98 %) and high diastereoselectivities for the trans-product (>95:5) starting either from readily accessible hydrazones, or from the corresponding aldehydes and substituted Boc-hydrazides in a one-pot process. The synthetic versatility of the tetrahydrophthalazine core was demonstrated by its straightforward conversion to dihydro-phthalazines, phthalazines, or pyrazolo dione derivatives. Furthermore, the N?N bond was reduced to afford a new route to 1,4-diamines.

Full text of DOI:10.1002/chem.201805249

A Journal of
Accepted Article
Title: Regiocontrolled and Stereoselective Syntheses of
Tetrahydrophthalazine Derivatives using Radical Cyclizations
Authors: Wei Zhang, Jia Yi Mo, Weiying He, Pierre Kennepohl, and
Glenn Martin Sammis
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To be cited as: Chem. Eur. J. 10.1002/chem.201805249
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Regiocontrolled and Stereoselective Syntheses of
Tetrahydrophthalazine Derivatives using Radical Cyclizations
Wei Zhang, Jia Yi Mo, Weiying He, Pierre Kennepohl, and Glenn M. Sammis*
Abstract: Tetrahydrophthalazine derivatives have found important
applications in pharmaceutical research, but existing synthetic
methods are unable to access them regio- and stereoselectively.
Herein, we present a new approach that addresses these challenges
by utilizing a 6-endo-trig radical cyclization in the key step. The
desired tetrahydrophthalazines can be accessed in high yields (55-
98%) and high diastereoselectivities for the trans-product (>95:5)
starting either from readily accessible hydrazones, or from the
corresponding aldehydes and substituted Boc-hydrazides in a one-
pot process. The synthetic versatility of the tetrahydrophthalazine
core was demonstrated by its straightforward conversion to dihydro-
phthalazines, phthalazines, or pyrazolo dione derivatives.
Furthermore, the N-N bond can readily be reduced to afford a new
route to 1,4-diamines.
Nitrogen heterocycles are prevalent in bioactive molecules and
represent 59% of the U.S. FDA approved small-molecule
drugs.[1,2] The pharmaceutical importance of these heterocycles
has led to substantial research into the development of new
Scheme 1. Strategies for the syntheses of phthalazine derivatives.
synthetic technologies for their preparation.[3] Considering the
vast diversity and variability of nitrogen-containing rings,[1,4] there
are still many pharmaceutically interesting substituted
We
hypothesized
that
we
could
directly
access
heterocycles that cannot be regio- and stereoselectively
accessed using existing synthetic technology. Two such
examples are di- (Scheme 1A, 2) and tetrahydrophthalazines (3),
which have been found to have important medicinal activities.[5]
These heterocycles are commonly accessed by first
synthesizing the requisite high-oxidation state phthalazine (1),
followed by sequential additions or reductions to afford the
desired reduced analogs (2 or 3)[5,6] This approach has two
limitations: it can be challenging to regioselectively synthesize
the starting phthalazine (1, if R1≠H) efficiently,[5e,6a-b,7] and there
is no demonstrated stereocontrol in the subsequent
addition/reduction steps.[5a,5e,6c-d] A more direct approach would
be a cyclization to form the diazene ring. There are only a few
examples of ionic cyclizations, including a Pictet-Spengler-type
cyclization (Scheme 1B)[ 8 ] and a silver-catalyzed cyclization
(Scheme 1C),[ 9 ] and they are limited to electron-rich arenes
(R1=electron donating groups), have a narrow substituent scope
at R2, or can only access specific substitution patterns (7). As a
result of all of these challenges, there are currently no efficient
and stereoselective routes to many substituted di- and
tetrahydrophthalazine analogs. Most notably, there are no
literature examples of stereoselective routes to 1,4-disubstituted
tetrahydrophthalazines (3).
tetrahydrophthalazine derivatives from a 6-endo-trig radical
cyclization of a suitably-substituted hydrazone (Scheme 1D, 8).
Unlike previous synthetic methods of phthalazine, this radical
cyclization method allows for complete control of substituents at
R1, R2, and R3, which provides a direct route to unsymmetric
phthalazine derivatives (1, 2, and 3). Furthermore, the
stereocenter in the starting material (8) may influence the
diastereoselectivity of the cyclization, allowing for
diastereoselective route to 1,4-disubstituted
tetrahydrophthalazines (3).
a
This radical cyclization is not only an unprecedented approach
for the syntheses of phthalazine derivatives, but also involves an
underexplored 6-endo cyclization onto a C=N bond. While many
synthetic studies have examined radical cyclizations onto C=N-R
containing functional groups, such as oximes,[10] imines,[11] and
hydrazones,[ 12 ] most of them have focused on the exo-
cyclizations.[13] There are no examples of 6-endo cyclizations
onto oximes, and the only 6-endo hydrazone cyclization was
demonstrated by our group in a method that featured cyclization
of a vinyl radical with a hydrazone to afford a transient
tetrahydropyradazine radical.[12w] Unfortunately, this method was
unsuccessful with aryl hydrazones, which are essential to
access
biologically
active
aryl-substituted
phthalazine
derivatives. We, therefore, sought to develop a new, general
[*]
Wei Zhang, Jia Yi Mo, Weiying He, Prof. Pierre Kennepohl, Prof.
Glenn M. Sammis
Department of Chemistry
method for the efficient 6-endo-trig cyclization of Boc-hydrazone
8.
University of British Columbia
2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
E-mail: gsammis@chem.ubc.ca
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To ensure optimized conditions would work for aryl substitution
at R2, we began our investigations into the radical cyclization of
optimization, we were able to achieve a one-pot process, with a
solvent switch, to afford the final product without any
degradation in yield (Scheme 2, 3a) compared to the two-step
protocol (Table 1, entry 10).
14
]
benzaldehyde-derived hydrazone 8a (Table 1).[
When
triethylborane was used as a radical initiator with slow addition
of tributyltin hydride, tetrahydrophthalazine 3a was formed in
poor conversion (entry 1). However, quantitative conversion was
achieved when the tin reagent was added in one portion (entry
With optimized conditions established, we next explored the
scope of this new cyclization methodology (Scheme 2). The
reaction afforded high isolated yields of the desired
tetrahydrophthalazine (3), regardless of whether the R2 arene
contained electron donating (3b) or electron withdrawing groups
(3c-3i).[17] The cyclization was also effective for heterocycles,
such as pyridine (3j-3k) and furan derivatives (3l), affording the
tetrahydrophthalazine products in 57-96% yield. Aliphatic
aldehydes were shown to be compatible in the reactions to form
alkyl tetrahydrophthalazine products (3m-3r) in good to excellent
yields regardless of steric hindrance. A substituted alkene could
also be tolerated in the sidechain (3r).[18] Glyoxylate-derived 3s
was also efficiently synthesized in 89% yield.
15
]
2). We next examined the less toxic[
reagent
tris(trimethylsilyl)silane (TTMSS)[16] and found that it could also
effectively promote the cyclization with comparable conversion
(entry 3), although the reaction was considerably slower. The
long reaction time could be significantly decreased by using an
elevated reaction temperature (entry 4).
Table 1. Optimization of the radical cyclization of hydrazone 8a.
Conversion
(%)[d]
Entry
x [H]
y (Et3B)
T (C)
t (h)
1[a][b]
2[a]
3[a]
4[a]
5[c]
1.5 equiv Bu3SnH
1.5 equiv Bu3SnH
10
10
10
10
10
10
10
5
-78rt
-78rt
-78rt
50
6
6
28
>95
3.0 equiv (TMS)3SiH
3.0 equiv (TMS)3SiH
3.0 equiv (TMS)3SiH
2.5 equiv (TMS)3SiH
2.0 equiv (TMS)3SiH
2.5 equiv (TMS)3SiH
2.5 equiv (TMS)3SiH
2.5 equiv (TMS)3SiH
52
6
91
>95
50
6
>95
6[c]
50
6
>95
7[c]
50
6
85
8[c]
50
6
>95
9[c]
2.5
5
50
6
54
10[c]
rt
1.5
>95 (87)[e]
All optimization reactions were run on 0.10 mmol scale and Et3B was
purchased as a 1.0 M solution in hexanes in inert atmosphere. Boc = tert-
butoxycarbonyl, rt = room temperature. [a] Reactions were run under N2
atmosphere with anhydrous toluene as the solvent. [b] [H] reagent was added
slowly as a 0.2 M solution in anhydrous toluene over 4 h. [c] Reactions were
run under air atmosphere with toluene that was not specially dried. [d]
Conversions to 3a were determined via 1H NMR spectroscopy of the crude
reaction mixture. [e] Isolated yield on 1.5 mmol scale.
Scheme 2. Syntheses of 1-substituted tetrahydrophthalazines from aldehydes
9 and hydrazide 2. Reactions were carried out on a 0.20 to 0.40 mmol scale
for 0.5 h to 3 h and Et3B was purchased as a 1.0 M solution in hexanes in inert
atmosphere. Boc = tert-butoxycarbonyl, rt = room temperature.
Further trials revealed that the reaction was sufficiently robust to
allow for comparable conversions using open-flask conditions
with toluene that had not been specially dried (entry 5).
Optimization of the equivalents of TTMSS (entries 6-7), triethyl
borane (entries 8-9), and temperature (entry 10) resulted in
conditions that could effect near-quantitative cyclization in only
1.5 hours at room temperature (entry 10). To improve the
efficiency of this cyclization process, we next investigated the
possibility of achieving more direct access to the
With the fundamental cyclization reactivity established, we next
examined the syntheses of unsymmetrical and 1,4-
disubstitutued tetrahydrophthalazine derivatives (Scheme 3).
The cyclization proceeded efficiently with either electron
withdrawing (3t) or electron donating groups (3u, 3v) on the
hydrazide arene. We then investigated the cyclization
diastereoselectivity starting with hydrazide derivatives with
tetrahydrophthalazine directly from the aldehyde.
After
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substitution at R3 (3w-3y).
Under our standard reaction
starting tetrahydrophthalazine can be selectively oxidized to the
corresponding dihydrophthalazine (2a) by treatment with NaH
and NCS, to afford the product in 72% yield.
conditions, we observed only a moderate yield of cyclized
product along with significant amount of uncyclized,
a
dehalogenated product. After a brief optimization, we were able
to effect the desired cyclization to achieve cyclized product 3w in
high yield exclusively as the 1,4-trans-diastereomer.[19] Similarly
good to high yields could be achieved with alkyl or aryl groups at
R2 and R3 (entries 3x, 3y) in very high diastereoselectivities.
To test the synthetic versatility of this new cyclization
methodology,
we
next
investigated
whether
the
tetrahydrophthalazine core could be converted into pyrazolo
dione 9, a key intermediate towards the synthesis of an active
central nervous system depressant (eq. 3).[5a] Gratifyingly, a
simple two-step sequence involving Boc deprotection followed
by treatment with malonyl chloride[22] afforded 9 in 45% yield.
Compared to existing synthetic routes, our new methodology
has the advantage of being able to selectively access
derivatives of 9 with substitution on the tetrahydrophthalzidine
arene. For example, methoxy-substituted product 10 can readily
be prepared in only 2 steps from cyclized product 3t (eq. 4) in
66% yield.
Scheme 3. Syntheses of multi-substituted tetrahydrophthalazines from
hydrazone 8. Reactions were carried out on 0.14 to 0.30 mmol scale for 30
min to 1.5 h. [a] Toluene/hexanes (10:1) were solvents. [b] MeOH/hexanes
(10:1) were solvents. Boc = tert-butoxycarbonyl, rt = room temperature.
Another
advantage
of
directly
accessing
the
tetrahydrophahalazine is that it provides a versatile and rapid
route to 1,4-diamine derivatives through N-N bond reduction (eq.
5). As a representative example, tetrahydrophahalazine 3c, can
be converted to the corresponding diamine (11) in high yield
using a one-pot process involving deprotection, followed by
reduction of the N-N bond,[23] and Boc protection.
To explain the observed diastereoselectivities, we conducted
computational studies on two cyclization pathways for substrate
8w leading to the trans and cis products. Calculations indicated
that the lowest energy transition states (TS) have boat-like
conformations with methyl at the pseudo-axial position to avoid
1,3-strain from Boc group (Figure 1). In the optimized transition
state (TS2) leading to the cis product, there is a significant steric
interaction between the phenyl group on the hydrazone and the
methyl group. This interaction is absent in the transition state
(TS1) leading to the trans product, which decreases the Gǂ by
approximatedly 5 kcal/mol.[20]
TS2
Cyclization ΔΔG2‡= 8.88 kcal/mol
TS1
Cyclization ΔΔG1‡ = 3.82 kcal/mol
Overall, we have developed a novel one-pot process for the
syntheses of tetrahydrophthalazines from aldehydes and
hydrazides utilizing a key 6-endo-trig radical cyclization onto a
hydrazone. Not only does this approach represent a new class
of radical cyclization onto hydrazones, but also it proved to be
an efficient, robust, and high yielding method to access
tetrahydrophthalazines regardless of the electronics of the
starting aldehydes. This new cyclization also provides the first
method for the highly stereoselective syntheses of trans-1,4-
Figure 1. The calculated transition states and corresponding energy barriers
of two pathways.
The oxidation state of the tetrahydrophthalazine rings can be
readily modified to access substituted phthalazines (eq. 1) and
dihydrophthalazines
(eq.
2).
Oxidation
of
the
tetrahydrophthalazine (3a) with DDQ affords desired phthalazine
1a in quantitative conversion and 99% yield.[21] Similarly, the
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tetrahydrophthalazines.
Further
synthetic
manipulation demonstrated versatility of the heterocycle
products as precursors to oxidized phthalazine analogs, such as
dihydro- and aromatic phthalazines, or to pyrazolo diones. The
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highlighted in a new route to 1,4-diamines. It’s anticipated that
our new methodology will provide access to a greater diversity of
these heterocycles and diamines for further pharmaceutical and
synthetic development.
Acknowledgements
This work was supported by the University of British Columbia
(UBC), the Natural Sciences and Engineering Research Council
of Canada (NSERC), the NSERC CREATE Sustainable
Synthesis Program, and a doctoral fellowship from UBC to W. Z.
Keywords: nitrogen heterocycle • tetrahydrophthalazine •
radical cyclization • hydrazone • synthetic methods
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10.1002/chem.201805249
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Entry for the Table of Contents
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Wei Zhang, Jia Yi Mo, Weiying He,
Pierre Kennepohl, and Glenn M.
Sammis*
Page No. – Page No.
Regiocontrolled and Stereoselective
Syntheses of Tetrahydrophthalazine
Derivatives using Radical Cyclizations
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