Terminal alkyne addition to diazodicarboxylates: Synthesis of hydrazide linked alkynes (ynehydrazides)

Article abstract of DOI:10.1021/ol2031608

A new route to form C_sp-N bonds has been developed via addition of in situ generated lithium acetylides to sterically hindered diazodicarboxylates. The reaction provides straightforward access to a previously unexplored ynehydrazide class of st

Full text of DOI:10.1021/ol2031608

ORGANIC
LETTERS
2012
Vol. 14, No. 2
540–543
Terminal Alkyne Addition to
Diazodicarboxylates: Synthesis of
Hydrazide Linked Alkynes
(Ynehydrazides)
Ramsay E. Beveridge and Robert A. Batey*
Davenport Research Laboratories, Department of Chemistry, University of Toronto,
80 St. George Street, Toronto, ON, Canada
rbatey@chem.utoronto.ca
Received November 25, 2011
ABSTRACT
A new route to form CspꢀN bonds has been developed via addition of in situ generated lithium acetylides to sterically hindered
diazodicarboxylates. The reaction provides straightforward access to a previously unexplored ynehydrazide class of stable N-linked alkynes
directly from commercially available precursors. Preliminary results show that alkynyl hydrazides are useful reagents for the selective installation
of nitrogen functional groups and as precursors to pharmaceutically relevant heterocycles using metal catalyzed cycloadditions and
condensations.
Over the past decade, N-functionalized ynamide alkyne
derivatives (Figure 1) have received considerable attention as
useful building blocks in organic chemistry, enabling selective
introduction of nitrogen functional groups in complex sys-
tems.1 Important features of these reagents include stability,
ease of preparation,2ꢀ4 and predictable reaction regioselec-
tivity due to the polarization of the alkyne bond. As a result,
Figure 1. Amide and hydrazide N-linked alkynes.
(1) For reviews on ynamides, see: (a) Evano, G.; Coste, A.; Jouvin, K.
Angew. Chem., Int. Ed. 2010, 49, 2840–2859. (b) DeKorver, K. A.; Li, H.;
Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev.
2010, 110, 5064–5106. (c) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.;
Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575–7606.
(2) From alkynyl-halides: (a) Frederick, M. O.; Mulder, J. A.; Tracy,
M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J.
J. Am. Chem. Soc. 2003, 125, 2368–2369. (b) Zhang, Y.; Hsung, R. P.;
Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151–
1154. (c) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz,
K. C. M.; Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen,
L.; Tracey, M. R. J. Org. Chem. 2006, 71, 4170–4177. (d) Dunetz, J. R.;
Danheiser, R. L. Org. Lett. 2003, 5, 4011–4014.
these amide-linked alkynes have been widely investigated in a
variety of reactions demonstrating value as privileged pre-
cursors for the synthesis of highly functionalized molecules
and biologically interesting heterocycle scaffolds,1,5 including
the total syntheses of natural products.6
(5) Selected recent examples of ynamide synthetic utility: (a) Kramer, S.;
Odabachan, Y.; Overgaard, J.; Rottlaender, M.; Gagosz, F.; Skrydstrup, T.
Angew. Chem., Int. Ed. 2011, 50, 5090–5094. (b) Schotes, C.; Mezzetti, A.
Angew. Chem., Int. Ed. 2011, 50, 3072–3074. (c) Mak, X. Y.; Crombie, A. L.;
Danheiser, R. L. J. Org. Chem. 2011, 76, 1852–1873. (d) Poloukhtine, A.;
Rassadin, V.; Kuzmin, A.; Popik, V. V. J. Org. Chem. 2010, 75, 5953–5962.
(e) Valenta, P.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2010, 132,
14179–14190. (f) Benoit, G.; Rudkin, M. E.; Lam, H. W. Org. Lett. 2010, 12,
2554–2557. (g) Banerjee, B.; Litvinov, D. N.; Kang, J.; Bettale, J. D.; Castle,
S. L. Org. Lett. 2010, 12, 2650–2652.
(3) From alkynyl-iodonium triflates: (a) Witulski, B.; Stengel, T.
Angew. Chem., Int. Ed. 1998, 37, 489–492.
(4) Other selected key ynamide synthesis examples: (a) Couty, S.;
Barbazanges, M.; Meyer, C.; Cossy, J. Synlett 2005, 905–910. (b)
Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–
835. (c) Bruckner, D. Tetrahedron 2006, 62, 3809–3814. (d) Coste, A.;
Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2009, 48,
4381–4385. (e) Jouvin, K.; Couty, F.; Evano, G. Org. Lett. 2010, 12,
3272–3275.
r
10.1021/ol2031608
Published on Web 01/04/2012
2012 American Chemical Society

Our interest in this area was driven by previous studies
on enamide7 and heterocycle synthesis in our laboratory,8
and a desire to develop approaches using both CꢀN bond
couplings and metal catalyzed heterocycle synthesis for the
construction of novel polyheterocyclic core structures. The
ynehydrazide functional group attracted our interest since,
despite the utility and popularity of ynamides, the related
dinitrogen ynehydrazine or ynehydrazide alkynes are vir-
tually unknown. The overall significance of hydrazine and
hydrazide functional groups in drug discovery research,9
the frequent use of hydrazine derivatives10 and alkynes11 as
precursors to heterocycles, and the application of NꢀN
bond cleavage to access amines/amides12 suggested that
ynehydrazides could serve as intriguing reagents for or-
ganic synthesis.
There are a few reports on the synthesis of trimethyl
substituted ynehydrazines,13 but these examples are not
amenable to providing differentially substituted hydrazine
derived functional groups (e.g., dinitrogen containing
heterocycles), and there exists only one example of an
ynehydrazide.14 We now report the development of
a general route to ynehydrazides and provide an
exploration of their chemistry, including their utility
for the selective synthesis of heterocyclic structures by
exploiting both alkyne and hydrazide functional groups
in ring-forming reactions. These studies demonstrate
that ynehydrazides are complementary reagents to
ynamides.
Based on the success of copper-promoted CspꢀN cross-
coupling approaches to generate ynamides,2 a similar strat-
egy was initially envisaged for ynehydrazide synthesis via
coupling of a suitably triprotected hydrazide with alkynyl
bromides (Scheme 1). Hydrazide 1 was chosen as a model
substrate since it could be readily generated from phthalic
anhydride in gram-scale quantities;15 however, under typical
copper-catalyzed or mediated ynamide synthesis condi-
tions, low yields of the desired ynehydrazides 2 were
observed (Scheme 1).
Despite their potential value as functionalized hydrazine
and heterocycle precursors, and as masked ynamides, a
general approach to ynehydrazide synthesis is not known.
(6) (a) Alayrac, C.; Schollmeyer, D.; Witulski, B. Chem. Commun.
2009, 1464–1466. (b) Couty, S.; Liegault, B.; Meyer, C.; Cossy, J.
Tetrahedron 2006, 62, 3882–3895. (c) Nissen, F.; Richard, V.; Alayrac,
C.; Witulski, B. Chem. Commun. 2011, 47, 6656–6658. (d) Nissen, F.;
Detert, H. Eur. J. Org. Chem. 2011, 2845–2853. (e) Zhang, Y.; Hsung,
R. P.; Zhang, X.; Huang, J.; Slafer, B. W.; Davis, A. Org. Lett. 2005, 7,
1047–1050.
(7) (a) Bolshan, Y.; Batey, R. A. Tetrahedron 2010, 66, 5283–5294. (b)
Bolshan, Y.; Batey, R. A. Angew. Chem., Int. Ed. 2008, 47, 2109–2112.
(8) Recent examples: (a) Joyce, L. L.; Batey, R. A. Org. Lett. 2009, 11,
2792–2795. (b) Viirre, R. D.; Evindar, G.; Batey, R. A. J. Org. Chem.
2008, 73, 3452–3459.
Scheme 1. A Copper-Promoted Hydrazide CspꢀN Cross-
Coupling Approach to Ynehydrazides
(9) For reviews on hydrazines and derivatives, see: (a) Schmidt,
E. W., Ed. Hydrazine and its Derivatives: Preparation, Properties,
Applications, 2nd ed.; John Wiley & Sons: New York, 2001. (b) Rademacher,
P. Sci. Synth. 2009, 40b, 1133–1210. (c) Rollas, S.; Kucukguzel, S. G.
Molecules 2007, 12, 1910–1939. (d) Hassan, A. A.; Shawky, A. M.
J. Heterocycl. Chem. 2010, 47, 745–763. (e) Ragnarsson, U. Chem.
Soc. Rev. 2001, 30, 205–213.
(10) For reviews on the use of hydrazines in heterocycle synthesis, see:
(a) Moulin, A.; Bibian, M.; Blayo, A.-L.; Habnouni, S. E.; Martinez, J.;
Fehrentz, J. A. Chem. Rev. 2010, 110, 1809–1827. (b) Humphrey, G. R.;
Kuethe, J. T. Chem. Rev. 2006, 106, 2875–2911. (c) Ganem, B. Acc.
Chem. Res. 2009, 42, 463–472. (d) Hughes, D. L. Org. Prep. Proced. Int.
1993, 25, 607–632. (e) Eicher, T.; Hauptmann, S.; Spiecher, A., Eds. The
Chemistry of Heterocycles, 2nd ed.; John Wiley & Sons: New York,
2004. (f) Fustero, S.; Simon-Fuentes, A. Org. Prep. Proced. Int. 2009, 41,
253–290. (g) Yet, L. Prog. Heterocycl. Chem. 2008, 19, 208–241.
(h) Withbroe, G. J.; Singer, R. A.; Sieser, J. E. Org. Process Res. Dev.
2008, 12, 480–489.
(11) Selected reviews: (a) Padwa, A., Ed. 1,3-Dipolar Cycloaddition
Chemistry; Pergamon Press: Oxford, 1984. (b) Padwa, A., Pearson, W. H.,
Eds. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
toward Heterocycles and Natural Products; John Wiley & Sons: New
York, 2002. (c) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644–4680.
(d) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875–2911. (e)
Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873–2920. (f) Zeni, G.;
Larock, R. C. Chem. Rev. 2004, 104, 2285–2309.
(12) Selected representative examples of hydrazine derivatives as
protected amines via NꢀN bond cleavage: (a) Eliminative cleavage:
Magnus, P.; Garizi, N.; Siebert, K. A.; Ornholt, A. Org. Lett. 2009, 11,
5646–5648. (b) Raney, Ni; Sinha, P.; Kofink, C. C.; Knochel, P Org.
Lett. 2006, 8, 3741–3744. (c) Oxidative cleavage: Fernandez, R.; Ferrete,
A.; Llera, J. M.; Magriz, A.; Martin-Zamora, E.; Diez, E.; Lassaletta,
J. M. Chem.;Eur. J. 2004, 10, 737–745. (d) Li/NH3: Brimble, M. A.;
Heathcock, C. H. J. Org. Chem. 1993, 58, 5261–5263. (e) SmI2: Ding, H.;
Friestad, G. K. Org. Lett. 2004, 6, 637–640 and references therein. (f) Pd/
C: Kim, Y. H.; Choi, J. Y. Tetrahedron Lett. 1996, 37, 5543–5546. (g)
Photochemical cleavage: Lebrun, S.; Couture, A.; Deniau, E.; Grand-
claudon, P. Synlett 2009, 2621–2624. (h) Zn/HOAc: Leblanc, Y.;
Zamboni, R.; Bernstein, M. A. J. Org. Chem. 1991, 56, 1971–1972.
(13) (a) De Croutte, H.; Janousek, Z.; Pongo, L.; Mere, R.; Viehe,
H. G. Bull. Soc. Chim. Fr. 1990, 127, 745. (b) Loffler, A.; Himbert, G.
Synthesis 1994, 383–386. (c) Himbert, G.; NaBhan, H.; Gerulat, O.
Synthesis 1997, 293–294.
An alternative approach was therefore considered
through which formation of the CspꢀN bond could be
achieved via addition of terminal acetylide nucleophiles to
readily available diazodicarboxylates (Scheme 2). Despite
the known examples of organometallic addition to these
electrophilic nitrogen sources,16 reaction of alkynyl nu-
cleophiles across the NdN bond of these species has not
been reported as a strategy to generate CspꢀN bonds. Such
an approach is a potentially attractive one given its gen-
erality, the availability of the reagents, and the stabilizing
(14) Denonne, F.; Seiler, P.; Diederich, F. Helv. Chim. Acta 2003, 86,
3096–3117.
(15) Brosse, N.; Pinto, M.-F.; Jamart-Gregoire, B. Eur. J. Org. Chem.
2003, 4757–4764.
(16) (a) Kkisseljova, K.; Tsubrik, O.; Sillard, R.; Maeorg, S.;
Maeorg, U. Org. Lett. 2006, 8, 43–45. (b) Uemura, T.; Chatami, N.
J. Org. Chem. 2005, 70, 8631–8634. (c) Beveridge, R. E.; Fernando, D.;
Gerstenberger, B. S. Tetrahedron Lett. 2010, 51, 5005–5008. (d) Demers,
J. P.; Klaubert, D. H. Tetrahedron Lett. 1987, 28, 4933–4934. (e)
Gerstenberger, B. S.; Rauckhorst, M. R.; Starr, J. T. Org. Lett. 2009,
11, 2097–2100. (f) Velarde-Ortiz, R.; Guijarro, A.; Rieke, R. D. Tetra-
hedron Lett. 1998, 39, 9157–9160. (g) Macklin, T. K.; Snieckus, V. Org.
Lett. 2005, 7, 2519–2522.
Org. Lett., Vol. 14, No. 2, 2012
541

yield (Scheme 2); however, use of the more sterically hindered
precursor di-tert-butylazodicarboxylate (DBAD) led to the
formation of ynehydrazide 3b in high yield (Scheme 2).17
This protocol was found to be quite general, and a wide
rangeofalkyneswerefoundtoundergo addition toDBAD
via the corresponding lithiated intermediates. The reaction
scope includes formation of aryl, heteroaryl, alkyl, benzyl,
and alkenyl substituted DBAD derived ynehydrazides 4
(Table 1). Isolated yields of these compounds are generally
good except for those containing electron-withdrawing
groups such as compounds 4cꢀe. In these cases, the use of
other metal acetylides did not improve reaction yields,18
potentially due to their inherently decreased nucleophilicity.
Also, commercially available terminal organometallic
acetylides did not yield the desired terminal ynehydrazides
using the above protocol. Similarly, ethyl propiolate was
not compatible with the metalation conditions. To over-
come these drawbacks, rapid TBAF mediated silyl group
deprotection of the TMS-protected ynehydrazides 3 pro-
vided a convenient route to terminal ynehydrazides 5 in
good yields (Scheme 3).17 Thus these products could then
be used as precursors to prepare other functionalized
ynehydrazides such as the ester 6, which was not directly
accessible through the lithium acetylide addition to diazo-
dicarboxylates.
Scheme 2. A Direct Formation of Ynehydrazide CspꢀN Bonds
via Lithium Acetylide Addition to Diazodicarboxylates
effects of the electron-withdrawing carbamate group on
the product ynehydrazides.
Initial results toward generating ynehydrazides using
in situ generated lithium acetylides with the commercially
available diethyl azodicarboxylate (DEAD) and dibenzyl
azodicarboxylate (DBnAD) resulted in complex reaction
mixtures and generated only trace amounts of ynehydra-
zide products. In these cases, acetylide addition to the
carbamate functional group instead of across the desired
NdN bond was observed as a major side product.
To avoid competitive addition to the carbamate more
sterically hindered diazodicarboxylate esters were employed.
Reaction of diisopropyl azodicarboxylate (DIAD) with TMS-
acetylide led to the isolation of ynehydrazide 3a in moderate
Table 1. Lithium Acetylide Addition to DBADa
Scheme 3. Synthesis of Terminal and Carbonyl Substituted
Ynehydrazides
Ynehydrazides 3ꢀ6 were observed to be generally quite
stable to silica gel chromatography and storage.19 Since
ynehydrazides are an almost unexplored compound class, a
study of their properties and synthetic utility was next under-
taken, with a focus on using the alkyne and hydrazide
functional groups for the formation of heterocycles of
potential medicinal relevance using metal catalyzed trans-
formations. The terminal ynehydrazides 5 underwent rt regio-
selective Cu-catalyzed “click-type” [3 þ 2] cycloadditions
(17) 3b could be obtained in similar yield on a 3 mmol scale; however,
an initial attempt to conduct the reaction on a larger scale led to a lower
yield of 3b. Batch preparation of 3b (2 ꢁ 3 mmol scale) was used for the
synthesis of terminal ynehydrazide 5a (see Supporting Information).
(18) Transmetalation of the lithium acetylide to copper (CuI) or zinc
(ZnCl2) before DBAD addition did not lead to a productive reaction.
Transmetalation to cerium (CeCl3) generated product but in 10% lower
yield than the Li-acetylide. Use of KHMDS in place of n-BuLi did not
lead to a productive reaction.
(19) The products could be stored on the bench for multiple weeks to
months without significant decomposition as monitored by TLC and 1H
NMR analysis, with the only exceptions being 4e and 4i which decom-
posed on the bench after 2 days. In these cases, however, freezer storage
(ꢀ10 °C) enhanced their life span to multiple weeks.
a n-BuLi (1.2 mmol) was added to alkyne (1.0 mmol) in THF (5 mL)
at ꢀ78 °C under N2, followed by addition of DBAD (1.5 mmol)
dissolved in THF (3 mL) and allowed to warm to rt over 30 min.
b1.2 equiv. LDA used instead of n-BuLi.
542
Org. Lett., Vol. 14, No. 2, 2012

Scheme 4. Synthesis of Hydrazide Functionalized Heterocycles
from Terminal Ynehydrazides
Scheme 6. One-Pot N-Heterocycle Functionalized Pyrazole and
Triazole Synthesis from Ynehydrazide Derived Heterocycles
a Combined yield of both pyrazole regioisomers; 3:1 in favor of the
one shown.
with 1,3-dipoles such as azides or nitrile oxides, enabling
selective hydrazide incorporation into 1,2,3-triazole (7) and
isoxazole (8) cores, respectively (Scheme 4). The 2-hydrazide
functionalized indole 9 was generated in moderate yield
through Pd-catalyzed Larock-type heterocyclization condi-
tions from 2-iodoaniline. These N-linked heterocycles are
interesting since they would be difficult to prepare under
alternative conditions (e.g., cross-coupling of hydrazides or
a nitration/reduction/diazotization sequence) and represent
previously unexplored heterocyclic cores. In addition, internal
ynehydrazides were found to undergo regioselective rt Ru-
catalyzed azide/alkyne cycloaddition20 to yield highly substi-
tuted hydrazide functionalized 1,2,3-triazoles 10 (Scheme 5).
toward our original goal of exploiting both alkyne and
hydrazine functional groups in orthogonal ring-forming
reactions. For example, N,N0-di-Boc hydrazide functional-
ized heterocycles such as 7a and 8 were rapidly transformed
into N-triazole and N-isoxazole functionalized pyrazoles 11
and 12 via simple addition of 1,3-dicarbonyls and anhy-
drous HCl (Scheme 6).16c,e In a related fashion, 1,2,3-
triazole 10a was directly converted in one pot to an unusual
N-1,2,3-triazole functionalized 1,2,4-triazole 13 via treat-
ment with formamide and anhydrous HCl. Overall, these
heterocycle targets would be difficult to disconnect via
alternative chemistry and demonstrate the significant prom-
ise of ynehydrazides for use in heterocycle synthesis.
Scheme 5. Formation of Hydrazide Functionalized 1,2,3-Tria-
zoles from Internal Ynehydrazides
In summary, a previously unexplored class of ynehydra-
zide heteroatom-linked alkyne reagents are demonstrated
to be stable, storable compounds which can be prepared
conveniently from commercially available alkynes and
diazodicarboxylates. Preliminary results demonstrate that
these compounds are useful reagents to selectively install
hydrazine units and convert them into medicinally impor-
tant heterocycles such as pyrazoles and 1,2,4-triazoles.
Further work on the reactivity of these interesting frag-
ments, including their use as masked ynamides, is ongoing
and will be reported in due course.
In agreement with Fokin’s observations of Ru-catalyzed 1,3-
dipolar cycloadditions of this type, a complete regioselectivity
switch is observed, providing exclusively the isomers shown.
Significantly, these DBAD derived hydrazide function-
alized heterocycles can be readily deprotected and applied
Acknowledgment. The authors thank the Natural Science
and Engineering Research Council of Canada (NSERC) and
the University of Toronto for financial support.
Supporting Information Available. Full experimental
details and characterization data for all compounds
(20) Boren, B. C.; Naravan, S.; Rasmussen, L. K.; Zhang, L.; Zhao,
H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923–
8930.
1
including H and 13C NMR. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 2, 2012
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