PIDA/TBAB-Promoted Oxidative Geminal Dibromofunctionalization of Alkynes: Direct Synthesis of Geminal Diazides

Article abstract of DOI:10.1002/ejoc.201801081

PIDA/TBAB-promoted oxidative geminal diazidofunctionalization of alkynes has been described for the first time. The transformation demonstrates a mechanistically distinctive approach to access geminal diazides, in which TBAB plays a crucial role as brominating agent and for the in situ generation of tetrabutylammonium azide. Furthermore, we have demonstrated here the first cycloaminative strategy by tactically employing the two azides groups leading to quinoxalines and synthesis of bis-triazole derivatives via copper catalysis.

Full text of DOI:10.1002/ejoc.201801081

A Journal of
Accepted Article
Title: PIDA/TBAB-Promoted Oxidative Geminal
Dibromofunctionalization of Alkynes: Direct Synthesis of Geminal
Diazides
Authors: Sagar Arepally, Venkata Nagarjuna Babu, Ashok Polu, and
Duddu S Sharada
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801081
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801081
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10.1002/ejoc.201801081
European Journal of Organic Chemistry
COMMUNICATION
PIDA/TBAB-Promoted Oxidative Geminal Dibromofunctionalization of
Alkynes: Direct Synthesis of Geminal Diazides
Sagar Arepallya, Venkata Nagarjuna Babua, Ashok Polua and Duddu S. Sharadaa*
Moreover, constructing these molecules from ample starting
materials is of great importance. Herein we disclose an
Abstract:
PIDA/TBAB-promoted
oxidative
geminal
diazidofunctionalization of alkynes has been described for the first
time. The transformation demonstrates a mechanistically distinctive
approach to access geminal diazides, in which TBAB plays a crucial
role as brominating agent and in insitu generation of
tetrabutylammonium azide. Further, we have demonstrated here the
first cycloaminative strategy by tactically employing the two azides
groups leading to quinoxalines and synthesis of bis-triazole
derivatives via copper catalysis.
unprecedented
phenyliodine
diacetate
(PIDA)/tetrabutylammonium bromide (TBAB) promoted
oxidative geminal dibromofunctionalization of alkynes with
primary amines and sodium azide (Scheme 1b) through
distinctive mechanism to access α,α-diazido β-iminoester
derivatives. As far as we know, this method demonstrates the
first example of PIDA/TBAB promoted diazidofunctionalization
of electron deficient alkynes to access synthetically and
biologically valuable geminal diazide substrates. Literature
survey showed that the reactivities of geminal diazides have not
been much established though only a few members of which
have been known.9,12 Apart from these reports, their utilization
for heterocycles synthesis is not much explored.13 In this context,
we have also demonstrated the versatility of geminal diazides via
a first cycloaminative approach towards quinoxalines and
synthesis of bis-triazole derivatives under copper catalysis.
Introduction
Organic azides serve as highly privileged compounds due to
its inherent reactivity and have found broad applications in
biological,1 pharmaceutical2 and materials science fields3 and are
versatile precursors for the synthesis of N-containing
heterocycles and functional group transformations.4 For
example, Huisgen “click” cycloadditions and Staudinger ligation
reactions are routinely used in chemical biology.5 Therefore, the
development of practical and efficient approaches for the
synthesis of functionalized organic azides is highly sought after.
In this direction, readily available alkynes serve as potential
building blocks for the preparation of organic azides.6 Among
which, difunctionalization of alkynes by simultaneous
introduction of various functional groups across the triple bond
has attracted great attention in recent years.7 In particular,
reductive azido-functionalization of alkynes is highly appealing
owing to the importance of resulting products in chemical
biology, drug discovery and various synthetic transformations.8
However, most of the reports on direct one-step
difunctionalization of the alkynes resulted in only olefins.6 A
general methodology is still lacking for the complete reductive
azido-functionalization of triple bond of alkynes to provide
functionalized alkanes. Pioneering work in this context, Yanada
et al.9 have reported the synthesis of diazidoketones (geminal
diazides) by reaction of aryl alkyl alkynes, N-iodosuccinimide
(NIS) and TMSN3 (Scheme 1a). However, lack of wide substrate
scope limits their application. Recently, Kirsch and co- workers
realized for the synthesis of the geminal diazides via direct
diazidation of 1, 3-dicarbonyls.10 However, there have been
limited number of methods known for the synthesis of geminal
diazides.11 Consequently, the development of efficient strategy
for the installation of multiple azide functionalities into new
molecules at one carbon is highly challenging.
Recently, we have reported dehydrogenative N-atom
installation into enamines promoted by organoiodine reagents
leading to diverse heterocycles in a selective manner.14 In these
transformations, the intrinsic property of iodine (III) reagents
enables to serve as an umpolung reagent or as an oxidant. During
our investigations in previous nitrogen incorporation strategies,
we have observed the interesting geminal diazide 3aa formation
in moderate yields (Table 1, entry 1) when tetrabutylammonium
bromide (TBAB) was used. Encouraged by this result we
focused on further investigations of geminal diazidative
functionalization of alkynes. We reasoned that this selective
chemical transformation in the presence of TBAB is due to the
rapid geminal dibromination of enamine β C(sp2)−H and
subsequent replacement of bromides by the azide nucleophile
(Scheme 3).
Scheme 1. Strategies for geminal diazido-functionalization of alkynes
Results and Discussion
[a]
Department of Chemistry, Indian Institute of
Technology Hyderabad,
Kandi – 502 285, Sangareddy, Telangana, INDIA
Phone: (040) 2301 7058; Fax: (040) 2301 6032,
E-mail:sharada@iith.ac.in
Our studies begun to improve the yield of 3aa. Initially, we
examined the reaction with different equivalents of TBAB
(Table 1 entries 2-5) in DCE as solvent, which indicates that
TBAB is required in excess amount to furnish the product in
good yield (entry 4). This supports our hypothesis of
dibromination followed by formation of geminal diazides. To
further check our assumption, we screened other
tetrabutylammonium salts, which surprisingly did not furnish the
desired geminal diazide product 3aa (Table 1, entries 6-9),
http://drsharadagroup.wixsite.com
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10.1002/ejoc.201801081
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instead we obtained the quinoxaline products via N-insertion.
While other nucleophilic halogen sources like KI, NaCl and
geminal diazidation reaction of amines 1 with different electron
deficient alkynes 2 (Table 2). Different alkynes (2a, 2b, 2c and
NH4Cl also failed to afford 3aa (Table S1, entries 1-3, see 2d) were tolerated and gave the corresponding products (3aa-
Supporting Information). From these experiments we can
conclude that PIDA might be unable to oxidize the halide ions
into halonium ions thus not affording the geminal dihalides and
hence the desired geminal diazides. On the contrary, in the
entries where we obtained quinoxalines along with geminal
diazides (Table 1, entries 1-3), we did further investigations,
wherein we subjected geminal diazides to optimized conditions
which did not afford the quinoxalines. Thus ruling out the
cycloaminative transformation of geminal diazides to
quinoxalines (Scheme S1, eq7, see SI). Furthermore halonium
sources such as NBS and NCS instead of TBAB also did not
furnish the product 3aa as we expected, however have afforded
the N-insertion products 3aa’ (Table S1, entries 4 and 5, see SI).
3rb, 3ac and 3ad) in good to excellent yields. Next, we turned
our attention to test the broad range of aromatic amines 1.
Aromatic amines 1 containing electron-neutral and electron-rich
functional groups have well reacted to afford the corresponding
α,α-diazido β-iminoester derivatives (3aa, 3ba, 3AB, 3db, 3bb,
3gb, 3ha, 3ia, 3ib, 3ma and 3nb) in excellent yields. Electron-
deficient halogen-substituted aryl amines worked well, pro-
vided the corresponding products (3ca, 3eb, 3ja, 3ka, 3jb and
3lb) in very good yields. Slightly lower yields were observed for
electron-withdrawing nitro- substituted aryl amine, which is due
to less formation of enamine or hydroamination product (3fb).
We sought to further explore this geminal diazidation reaction,
to our delight, aliphatic amines were found to be compatible for
hydroamination-diazide transfer reaction sequence (3pa, 3qb
and 3rb). Furthermore, we explored the scope with those
enamines which are not possible to generate insitu under mild
conditions, which afforded the respective geminal diazide
products in moderate yields (3ac and 3ad). To validate the
efficiency of this protocol, we carried out the gram-scale
synthesis under optimized reaction conditions resulting in 3aa in
78% yield.
Table 1. Optimization of the reaction conditions for the formation of
α,α-diazido β-iminoester 3aaa
entry
iodine reagent
(equiv)
[N3] source
(equiv)
additives
(equiv)
yield
(3aa%)b
yield
(3aa’%)b
Table 2. Substrate scope of amines and alkynesa,b
1
2
PhI(OAc)2 (2.5)
PhI(OAc)2 (2.5)
PhI(OAc)2 (2.5)
PhI(OAc)2 (2.5)
PhI(OAc)2 (2.5)
PhI(OAc)2 (2.5)
PhI(OAc)2 (2.5)
PhI(OAc)2 (2.5)
PhI(OAc)2 (2.5)
-
NaN3 (2.5)
NaN3 (2.5)
NaN3 (2.5)
NaN3 (2.5)
NaN3 (2.5)
NaN3 (2.5)
NaN3 (2.5)
NaN3 (2.5)
NaN3 (2.5)
NaN3 (2.0)
TBAN3 (2.0)
NaN3 (4.0)
TBAB (1.0)
TBAB (0.5)
TBAB (1.5)
TBAB (2.0)
TBAB (2.5)
TBAI (2.0)
TBAF (2.0)
TBACl (2.0)
BTAC
55
23
61
74
75
-
15
39
12
-
3
4
5
-
6
65
20
43
62
7
-
8
-
9
-
c
10
11
12
TBAB (2.0)
-
-
-
d
-
39
91
-
PhI(OAc)2 (3.0)
TBAB (2.0)
-
aReaction conditions: 1a (1.0 equiv), 2a (1.0 equiv), dry solvent (0.25 M), 25
°C, 14 h. bIsolated yields. cHydroamination product isolated. dNBS (N-
bromosuccinamide) (1.5 equiv) used as additive. TBACl = tetrabutylammonium
chloride. BTAC = Benzyltriethylammonium chloride
In the absence of PIDA, the reaction did not proceed (Table 1,
entry 10) indicating that PIDA’s role as an oxidant for the azido-
functionalization reaction. Although other combination15
alternative to PIDA resulted in the 3aa, the yield of the product
was low (Table 1, entry 11). Lowering the amount of PIDA and
sodium azide to 2.0 equiv decreased the yield to 65 % (Table S1,
entry 6, see SI). Next, we have screened the reaction by
increasing the equivalents of PIDA and NaN3 (Table S1, entries
7-10, see SI). We are delighted to find geminal diazide 3aa in
91% yield with 3.0 equiv of PIDA and 4.0 equiv of NaN3 in DCE
solvent (Table 1, entry 12). Among various iodine reagents
examined, PIDA gave the product 3aa in 91 % whereas other
oxidants failed to give the desired product (Table S2, see SI). The
use of other N3-sources such as TMSN3 and 1-azido-1,2-
benziodoxol-3-(1H)-one IBA-N3, and other combinations15 in
the absence of PIDA were not successful (Table S1, entries 11-
15, see SI)). The solvent evaluation studies showed that DCE is
the most suitable solvent (Table S3, entry 2, see SI). After
optimization of the reaction conditions, we next examined the
aReactions were performed using 1a (1.0 equiv), 2a (1.0 equiv), PIDA (3.0
equiv), NaN3 (4.0 equiv), TBAB (2.0 equiv) and dry DCE (0.25 M) at 25 °C for 8
to 14 h. bYields after silica column chromatography.
Having demonstrated the scope of the protocol, a series of
experiments were carried out to investigate this interesting
reaction mechanism. The reaction has failed to furnish the
desired product 3aa in the absence of either PIDA or TBAB
(Scheme 2, eq1 and 2), suggesting both PIDA and TBAB are
crucial for this transformation. To investigate the possible radical
pathway, we performed the reaction with 2,2,6,6-tetramethyl-1
piperidinyloxy (TEMPO) and 4-OH-TEMPO as radical
inhibitors, which resulted in complex mixture with decreased
yields of product 3aa (21% and 25%) and enamine 2aa (18%
and 15%) (SchemeS1, eq1 and 2, see SI). However, the results
are not conclusive as there is no complete inhibition of the
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10.1002/ejoc.201801081
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product 3aa formation and the presence of unreacted enamine
2aa. To further evaluate the radical pathway, we performed a
radical clock experiment under standard conditions, which gave
only the geminal diazide product 3rb, and no other ring-opened
coupling products were observed (eq3, see SI). These
experiments suggested that reaction might proceed through the
ionic mechanism.
in quinoxaline derivatives 4a-4f in good yields (Table 3).
Geminal diazides with the unsymmetrically substituted aryl ring
(3sa) furnished the mixture of isolable regioisomers (4f and 4f’).
Further, the gram scale synthesis of quinoxalines also
demonstrates the scalability and general applicability of this
method.
Scheme 3. Plausible Mechanism
Scheme 2. Control experiments
Table 3. Synthesis of quinoxaline compoundsa, b
Accordingly, we assumed that bromide ion can be converted
into bromonium ion by oxidant PIDA, which in turn undergoes
electrophilic addition to enamine C(sp2)–H resulting in the key
intermediate 3AB. To verify this possibility, we presumed to use
other non-nucleophile sources such as NaNO2 and NaNO3
instead of NaN3 to isolate intermediate 3AB. Consequently, we
obtained geminal dibromide 3AB (Scheme 2, eq3). Then we next
performed the reaction of geminal dibromide 3AB with NaN3,
which failed to provide desired product 3aa (eq4, see SI). To
assess the role of PIDA and TBAB, we carried out few control
experiments with geminal dibromide 3AB (eq5, see SI). Among
these experiments, only the reaction of 3AB with NaN3 and
TBAB gave the geminal diazide 3aa in 93% yield (Scheme 2,
eq4). Furthermore, we performed the reaction of geminal
dibromide 3AB with tetrabutylammonium azide, which also
resulted in geminal diazide 3aa (Scheme 2, eq5). We have also
performed the reaction under standard conditions with geminal
dibromide 3AB, which resulted only the geminal diazide 3aa in
91% yield (eq6, see SI). These experiments and NMR
experiments16 suggested that TBAB is not only the brominating
reagent but it also plays a key role in the nucleophilic
replacement.
aReactions were performed using 3 (1.0 mmol), Cu(OTf)2 (10 mol%) and dry
toluene at 120 °C for 18 h. bIsolated yields after silica column chromatography.
Furthermore, we have also presented the copper catalyzed
azide-alkyne cycloaddition (click reaction) owing to the wide
applications in material and surface sciences.19 In this strategy,
two azide groups of geminal diazides (3a to 3j) reacted with
terminal alkynes (5a to 5c) to afford bis-triazole derivatives with
very good (Table 4, 6aa to 6jc).
Table 4. Synthesis of bis-triazole compoundsa, b
On the basis of above experimental results, and literature
studies,17 we proposed the plausible mechanism as shown in
scheme 3. An oxidation of bromide ion by PhI(OAc)2 in the
presence of NaN3 would provide the bromonium ion which
undergoes a direct electrophilic addition to β-C(sp2)-H of
hydroamination product I to generate reactive intermediate 3AB.
The intermediate 3AB would undergo nucleophilic replacement
by basic N3 anion from insitu generated tetrabutylammonium
azide to afford the product 3aa.
After successfully synthesis of geminal diazides, we have
determined the thermal stabilities of few of selected compounds
3aa, 3db, 3ja, 3ka and 3ta from DSC experiments in the regard
of safety concerns when handling these diazides (TableS4, see
SI).10b,18 Accordingly, we have demonstrated their synthetic
utility. Delightfully, we report herein a cycloaminative strategy
in which the two-azide groups have been employed wherein one
azide group serves as N-source by the formation of nitrene while
another azide group is sacrificed for the aromatization resulting
aReactions were performed using 3 (1.0 mmol), 5 (2.5 mmol) and CuI (10 mol%)
in CH3CN at 70 °C for 12-24 h. bIsolated yields after silica column
chromatography.
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Conclusions
In conclusion, the first example of PIDA/TBAB-promoted
geminal diazido-functionalization of alkynes under mild reaction
conditions to access valuable α,α -diazide β-iminoester
derivatives is disclosed here. The transformation features two
azides and one amine groups transfer across the triple bond of
alkyne to install two C-N bonds on each carbon in one reaction.
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This method demonstrates
a mechanistically distinctive
approach to complete reductive functionalization of alkynes by
the addition of two different nucleophiles. Further, we explored
the utility of synthesized geminal diazides in copper-catalyzed
cycloamination for the synthesis of quinoxalines and bis-triazole
derivatives. Further studies of geminal diazides are currently
under way in our laboratory.
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Experimental Section
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Amine 1 (1 mmol) was taken in a dried 10 mL round bottom
flask, and alkyne 2 (1 mmol) was added slowly in DCE (0.5 mL)
solvent, and the reaction mixture was stirred (if required) at room
temperature for 10 min to 3 h. After the formation of
hydroamination product (confirmed by TLC); solvent DCE (0.25
M, based on hypervalent iodine), tertrabutylammonium bromide
(TBAB) (2 mmol) and NaN3 (4 mmol) were added, followed by
addition of phenyliodo(III)diacetate (PIDA) (3 mmol) in portion
wise for 30 min. The progress of the reaction was monitored by
TLC till the reaction is completed (4-14 h). The reaction mixture
was quenched by addition of saturated solution of NaHCO3 and
extracted with ethyl acetate, dried over MgSO4, and concentrated
in vacuo. The residue was purified through a silica gel column
using petroleum ether/ethyl acetate (9.8:0.2) as eluent. All the
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1
compounds 3aa to 3ta were confirmed by FTIR, H NMR, 13C
NMR and HR-MS spectral analyses.
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AUTHOR INFORMATION
Corresponding Author
* E-mail: sharada@iith.ac.in
ACKNOWLEDGMENTS
[13] a) H. Erhardt, K. A. Kunz, S. F. Kirsch, Org. Lett. 2017, 19, 178; b) F.
Ballaschk, H. Erhardt, S. F. Kirsch, RSC Adv. 2017, 7, 55594.
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5014; b) A. Sagar, S. Vidyacharan, A. H. Shinde, D. S. Sharada, Org.
Biomol. Chem. 2016, 14, 4018.
We gratefully acknowledge the Department of Science and
Technology-Science and Engineering Research Board (DST-SERB-
EMR/2016/1000952) New Delhi, India and Indian Institute of
Technology Hyderabad (IITH) for financial support. SA thanks
CSIR, VNB thanks UGC New Delhi, AP thanks DST-SERB India
for the award of research fellowship. We thank P.Vijay Kumar for
DSC measurements.
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Anderson, X. Bi, Angew. Chem. Int. Ed. 2017, 56, 13805.
[16] We have also performed NMR experiments of i) PIDA and NaN3; ii) PIDA,
NaN3 and TBAB for more insights into the reaction mechanism (see SI).
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L. Li, C. Xing, J. Org. Chem. 2015, 80, 10000.
Keywords: diazidofunctionalization; geminal diazides;
dibromofunctionalization; cycloaminative; quinoxalines; bis-
triazoles.
[18] The decomposition temperatures of our synthesized geminal diazides 3aa,
3db, 3ja, 3ka and 3ta are mostly similar to that of geminal diazides
derived from 1, 3-dicarbonyls (ref: 10b) as reported by Kirsch research
group. The decomposition temperatures are given as onset
temperatures (TableS4, see SI).
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Wiley: Chichester, West Sussex, UK, 2010; b) S. Brase, C. Gil, K.
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10.1002/ejoc.201801081
European Journal of Organic Chemistry
COMMUNICATION
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COMMUNICATION
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COMMUNICATION
Organic Azides
Sagar Arepally, Venkata Nagarjuna
Babu, Ashok Polu and Duddu S.
Sharada
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PIDA/TBAB-Promoted oxidative
Geminal Dibromofunctionalization of
Alkynes: Direct Synthesis of Geminal
Diazides
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PIDA/TBAB-promoted oxidative geminal dibromination-diazidation sequence provides straightforward access to geminal
diazides. In this transformation, TBAB plays a crucial role as brominating agent and in insitu generation of
tetrabutylammonium azide. Further, we have presented the synthetic utility of geminal diazides by the synthesizing
quinoxalines and bis-triazoles via copper catalysis.
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