Davis-Beirut Reaction: Alkoxide versus Hydroxide Addition to the Key o-Nitrosoimine Intermediate

Article abstract of DOI:10.1021/acs.orglett.8b00036

Reaction options, alkoxide vs hydroxide vs amine addition to the key intermediate (o-nitrosoimine) generated in the Davis-Beirut reaction of an o-nitrobenzylamine substrate, are reported to explain the nucleophilic addition selectivity of this one-pot ind

Full text of DOI:10.1021/acs.orglett.8b00036

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Davis−Beirut Reaction: Alkoxide versus Hydroxide Addition to the
Key o‑Nitrosoimine Intermediate
†
†
†
†
†
Jie S. Zhu, Matthew R. Duong, Andrew P. Teuthorn, Julia Y. Lu, Jung-Ho Son,
‡
,†
Makhluf J. Haddadin, and Mark J. Kurth*
†Department of Chemistry, University of California Davis, 1 Shields Avenue, Davis, California 95616, United States
‡Department of Chemistry, American University of Beirut, Beirut 1107 2020, Lebanon
*
S Supporting Information
ABSTRACT: Reaction options, alkoxide vs hydroxide vs
amine addition to the key intermediate (o-nitrosoimine)
generated in the Davis−Beirut reaction of an o-nitrobenzyl-
amine substrate, are reported to explain the nucleophilic
addition selectivity of this one-pot indazole-forming process.
The hydroxide addition/deprotection pathway as well as the
fate of the resulting o-nitrosobenzaldehyde were both
uncovered with several o-nitrobenzylamine substrates, and
design elements required for an efficient double Davis−Beirut
reaction, inspired by new mechanistic insights, were defined.
number of versatile protocols have been developed for
attack by alkoxide, which then triggers an N−N-bond forming
reaction that results in formation of indazole product 4.
One unanswered mechanistic question in this 1 → indazole 4
process is why does alkoxide outcompete hydroxide in addition
to the key o-nitrosoimine intermediate? The origin of this
“alkoxide over hydroxide” selectivity is ambiguous since
addition of water (and hydroxide) to imines, i.e., the first
step in imine hydrolysis, represents a fundamental reaction in
organic chemistry. Our recent work on exploiting alternative
A
N−N bond formation, with beneficial applications to a
1
variety of intriguing heterocyclic targets. One of these targets,
2
indazoles, exhibit a wide range of biological activities and
reactivities, for example, readily undergoing rearrangement in
3
the presence of electrophiles to indazolones, which also have
4
considerable potential as biologically relevant targets. The
5
versatile Davis−Beirut reaction provides a robust method for
2
the construction of indazoles and has been extensively studied
6
7
experimentally and computationally. The proposed Davis−
chemistries of Davis−Beirut reaction intermediates caused us
Beirut mechanism (Scheme 1) involves generation of transient
o-nitrosoimine intermediate 2 by treatment of o-nitrobenzyl-
amine 1 with hydroxide. The imine moiety in 2 is susceptible to
to consider other possible reactions of transient o-nitrosoimine
2. In one hypothesized side reaction, 2 reacts with hydroxide
(or water) to form hemiaminal 5, which can subsequently
collapse to o-nitrosobenzaldehyde 6 (Scheme 1). Indeed, this
previously overlooked 2 → 6 reversible process provides a
mechanistic model, which underscores the question of alkoxide
vs hydroxide chemoselectivity in the Davis−Beirut reaction.
Herein, we unveil these mechanistic details through inter-
mediate trapping strategies and insights gained from “double”
Davis−Beirut reactions.
Scheme 1. Davis−Beirut and Deprotection Reactions of o-
Nitrosoimine 2
The o-nitrobenzyl group is a well-known photolabile
8
protecting group for heteroatoms where each deprotection
9
event generates a molecule of o-nitrosobenzaldehyde. If a 2 →
5
→ 6 process is indeed occurring during the Davis−Beirut
reaction, the resulting o-nitrosobenzaldehyde could be trapped
by reacting with the primary amine liberated during the
formation of 6 to regenerate 2. Therefore, it can be anticipated
that less nucleophilic amines, like aniline, released in 2 → 6
would not successfully compete in an “added amine”
experiment, for example, where added n-butylamine could
Received: January 4, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
trap released o-nitrosobenzaldehyde. Indeed, when N-(2-
nitrobenzyl)aniline was reacted under standard Davis−Beirut
reaction conditions but with 15 equiv of added n-butylamine,
Scheme 2. Reaction Options Confronted by Transient o-
Nitrosoimine 2
1
H NMR of the crude reaction mixture showed the presence of
both N-phenylindazole, via the normal uninterrupted Davis−
Beirut reaction, and N-butylindazole, via the o-nitrosobenzalde-
R=n‑butyl
hyde pathway and subsequent 6 → 2
(Table 1, entry 1).
Table 1. Amine Exchange in the “Added Amine” Davis−
a
Beirut Reactions
a
1
See the SI for the crude H NMR data for Table 1, entries 1−3.
b
1
Determined by H NMR analysis of the crude reaction mixture.
undergo N−N-bond formation to indazolone 7 (trace amounts
detected by LCMS) or loss of amine to o-nitrosobenzaldehye
(
6; i.e., deprotection). The implications of the data in Table 1
When water was excluded from the added amine reaction, the
o-nitrosoimine intermediate was not expected to hydrolyze to a
significant extent and, indeed, only the N-phenylindazole was
observed (entry 2). Moreover, there is a relatively demanding
steric environment at the imine carbon of o-nitrosoimine
intermediate 2 as evidenced by failure of the Davis−Beirut
are that liberated o-nitrosobenzaldehyde (6 in Scheme 2) can
condense with the added amine (H NR ) to regenerate N-
alkyl-1-(2-nitrosophenyl)methanimine 2 or lead to the
formation of minor undetermined side products.
1
2
1
2
With these results as backdrop, we next set out to isolate the
amine released when water or hydroxide adds to intermediate 2
(Scheme 1). However, when typical Davis−Beirut substrates
undergo deprotection (i.e., 1 → 6; Scheme 1), isolating the
resulting relatively low molecular weight amine is complicated
by the reaction workup sequence. A “double” Davis−Beirut
substrate (10 in Scheme 3a) was developed to mitigate this
issue since deprotection product 12 would be highly
compatible with the employed experimental procedures and
analytical methods, such as TLC and LCMS. When substrate
10 was subjected to standard Davis−Beirut reaction conditions,
indazolylamine 12, the cumulative consequence of one Davis−
Beirut reaction (10 → 13 or 11 → 12) and one deprotection
reaction (10 → 11 or 13 → 12), was isolated in appreciable
quantities (30% yield), indicating that deprotection can indeed
be a competing process. Bis-indazole 14, the cumulative
consequence of two Davis−Beirut reactions (10 → 13 → 14),
was a minor product (6% yield) in this reaction. These 10 →
12 + 14 results were mirrored in several other double Davis−
Beirut reactions (→ bis-indazoles 16−19; Scheme 3b),
although in quite variable yields.
10
reaction when bulky alcohols like isopropanol are employed.
As a result, we anticipated trapping of the liberated o-
nitrosobenzaldehyde with the less hindered of the two
competing alkyl amines in this added amine experiment.
Indeed, when N-(2-nitrobenzyl)isopropylamine was subjected
to the Davis−Beirut reaction with 15 equiv of added n-
butylamine, both N-isopropyl- and N-butylindazoles were
observed (entry 3). Finally, when N-(2-nitrobenzyl)butan-1-
amine was employed as the starting material, neither added
excess aniline nor isopropylamine were competitive, and only
N-butylindazole was detected (entries 4 and 5).
The starting o-nitrobenzylamines (1) are readily prepared by
amine N-alkylation with o-nitrobenzyl bromide (Scheme 2).
13
Upon treatment with KOH in ROH/H O (simple alcohols like
2
MeOH and EtOH work best), an internal oxidation (benzylic
amine → benzylic imine) reduction (nitro → nitroso) reaction
takes place to deliver N-alkyl-1-(2-nitrosophenyl)methanimine
2. In the added amine experiment, this key intermediate
confronts three potential nucleophiles: (i) alkoxide (→ 1-(2-
nitrosophenyl)methanamine 3); (ii) hydroxide (→ (2-
nitrosophenyl)methanol 5); and (iii) added amine (→ 1-(2-
nitrosophenyl)methanediamine 8). Since a 1°-amine is an order
of magnitude less nucleophilic than a simple alkoxide (like
As a further probe of transfomation dynamics in the bis-
1
2
indazole-forming process, N ,N -bis(2-nitrobenzyl)ethane-1,2-
diamine (15), the substrate leading to bis-indazole 16, was
subjected to Davis−Beirut conditions where various amounts of
water were employed (Figure 1). The presence of at least ∼5%
water in methanol is clearly advantageous, but the upper limit
of beneficial effects seemed to be at about 15−20% added water
as a downward trend in yield was observed with each
incremental increase past ∼20% added water.
Although the double Davis−Beirut reactions delineated in
Scheme 3 served the purpose of illuminating a much more
complete mechanistic model for this indazole-forming reaction,
the low bis-indazole product yields were, nonetheless,
11
methoxide or ethoxide) and since no trace of 9 (or its
tautomers) is detected in the crude reaction mixture, we
concluded that 2 → 8 is a nonviable pathway when the reaction
11
6
is run in methanol or ethanol. Alkoxide addition 2 → 3 is the
preferred pathway, delivering indazole 4 in generally excellent
1
yield (for example, when R = isopropyl, indazole 4 is obtained
in 87% overall yield from o-nitrobenzyl bromide). Competing
hydroxide addition to intermediate 2 is a viable, but minor,
pathway that leads to (2-nitrosophenyl)methanol 5, which can
B
DOI: 10.1021/acs.orglett.8b00036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Scheme 3. Double Davis−Beirut Reactions: (a) Contending
Scheme 4. Substrate 21, Which Provides Two Internal
Nucleophiles, Results in a High-Yielding Double Davis−
Beirut Transformation
a
Pathways and (b) Bis-indazole Examples
In conclusion, the work reported here decrypts the issues
involved in alkoxide vs hydroxide selectivity in the Davis−
Beirut reaction. The hydroxide addition/deprotection pathway
and the role of o-nitrosobenzaldehyde were both delineated
with several o-nitrobenzylamine substrates, and design elements
required for an efficient double Davis−Beirut reaction, inspired
by new mechanistic insights, were defined.
ASSOCIATED CONTENT
Supporting Information
■
*
S
a
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00036.
The generally improved double Davis−Beirut product yields for 16−
1
9 vs 14 perhaps reflect the increased nucleophilicity of MeOH vs
11
EtOH.
1
Experimental procedures, characterization data, and H
and 13C NMR spectra (PDF)
Accession Codes
CCDC 1813045−1813046 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Figure 1. Yield consequence of added water in double Davis−Beirut
reaction 15 → 16.
*
E-mail: mjkurth@ucdavis.edu.
ORCID
Jie S. Zhu: 0000-0003-3009-4135
Mark J. Kurth: 0000-0001-8496-6125
Notes
disappointing. However, the mechanistic insights gained with
these substrates were exploited to design double Davis−Beirut
substrate 21 [prepared by reductive amination of o-nitro-
benzaldehyde with 2,2-bis(aminomethyl)propane-1,3-diol
The authors declare no competing financial interest.
1
4
(
20); Scheme 4], which was expected to perform optimally
ACKNOWLEDGMENTS
in bis-indazole formation. Specifically, since diaminodiol 21
contains an internal nucleophile for each Davis−Beirut
transformation in 21 → 22, this substrate effectively over-
whelmed intermolecular with intramolecular nucleophilic
additions to the two short-lived o-nitrosoimine intermediates,
and indeed, 21 was converted to spiro-fused bis-indazole 22 in
an impressive 72% yield, which translates to 85% yield per
Davis−Beirut reaction.
■
We gratefully acknowledge financial support from the National
Institutes of Health (DK072517 and DK067003) and the UC
Davis Tara K. Telford CF Fund (fellowship to J.S.Z.).
DEDICATION
■
We dedicate this work in memory of Dorothy J. Schoening, a
wonderful and gracious mentor.
C
DOI: 10.1021/acs.orglett.8b00036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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DOI: 10.1021/acs.orglett.8b00036
Org. Lett. XXXX, XXX, XXX−XXX