Boron-containing enamine and enamide linchpins in the synthesis of nitrogen heterocycles

Article abstract of DOI:10.1021/ja510963k

The use of α-boryl enamine and enamide linchpins in the synthesis of nitrogen heterocycles has been demonstrated. Boryl enamines provide ready access to the corresponding α-halo aldehydes, which undergo regioselective annulation to form borylated thiazole

Full text of DOI:10.1021/ja510963k

Article
pubs.acs.org/JACS
Boron-Containing Enamine and Enamide Linchpins in the Synthesis
of Nitrogen Heterocycles
Jeffrey D. St. Denis, Adam Zajdlik,† Joanne Tan,† Piera Trinchera, C. Frank Lee, Zhi He, Shinya Adachi,
and Andrei K. Yudin*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada
M5S 3H6
S
* Supporting Information
ABSTRACT: The use of α-boryl enamine and enamide linchpins in the synthesis of nitrogen heterocycles has been
demonstrated. Boryl enamines provide ready access to the corresponding α-halo aldehydes, which undergo regioselective
annulation to form borylated thiazoles. A condensation/amidation sequence converts α-boryl aldehydes into stable α-boryl
enamides without concomitant C → N migration. We also show that palladium-catalyzed cyclization of α-boryl enamides leads to
synthetically versatile isoindolones. These molecules can be subsequently used to access polycyclic scaffolds.
INTRODUCTION
■
Innovative approaches to new synthetic transformations are
likely to emerge by thorough consideration of underutilized
combinations of functional groups in reaction substrates.1 In
this regard, advances in catalysis directed toward chemical
synthesis would benefit from the rational deployment of novel
metal- and metalloid-containing intermediates. Our recent
explorations in the area of kinetically amphoteric molecules
have led to α-boryl aldehydes,2 which have opened doors to
Figure 1. B−C−C−N motifs in nitrogen heterocycle synthesis.
several other amphoteric species.3 As part of this investigation,
we reported the first example of C−B fragment migration
driven by the Curtius rearrangement.4 Since then, we have
reactions that proceeded without premature engagement of the
C−B bond.2 The use of the N-methyliminodiacetyl (MIDA)
pursued the application of densely functionalized boron-
ligand enforces sp3-hybridization at boron, shielding it from
containing building blocks with the goal of exploiting
external Lewis bases,5 which has allowed us to gain access to a
uncommon intermediates toward the synthesis of nitrogen-
containing heterocycles. A particularly intriguing possibility has
been to explore the synthesis and application of B−C−C−N
range of novel intermediates.6 We now demonstrate that α-
boryl enamines are useful in the synthesis of α-halogenated
boryl aldehydes. These products are amenable to annulation to
motifs as synthetic linchpins (Figure 1). This would help realize
form 2,5-disubstituted boryl thiazoles. Moreover, we show that
one of our long-standing objectives in the area of amphoteric
reactivity: engagement of both nucleophilic and electrophilic
reactivity nodes in the same sequence.
When it comes to carbon−carbon bond formation, organo-
boron reagents are among the pillars of organic synthesis.
Notably, α-boryl carbonyl species (C-bound boron enolates)
have rarely been described, which is due to their inherent
α-boryl enamides act as linchpin reagents in intramolecular
Suzuki−Miyaura cross-coupling (SMCC) and Heck coupling at
the β C−H bond (Figure 1).
RESULTS AND DISCUSSION
Pyrrolidine-Catalyzed Route to Boryl Enamines and
Their α-Halogenation. As part of our effort in exploiting the
■
instability and favorable tautomerization to the O-bound boron
enolates.3 In 2011, we reported the preparation of kinetically
stable amphoteric α-boryl aldehydes (C-bound boryl carbonyl
species) and systematically explored aldehyde functionalization
Received: October 24, 2014
Published: November 25, 2014
© 2014 American Chemical Society
17669
dx.doi.org/10.1021/ja510963k | J. Am. Chem. Soc. 2014, 136, 17669−17673

Journal of the American Chemical Society
Article
chemistry of B−C−C−N motifs, we have pursued the parent
(or unsubstituted) α-MIDA boryl aldehyde 1 (Figure 2).
Application of the bromination protocol to a variety of
substituted α-boryl aldehydes was then explored (Scheme 1).
Both electron-rich and electron-poor aryl substrates as well as
alkyl derivatives were smoothly converted to the α-brominated
products in good yields. The corresponding chlorinated
compounds were readily obtained by substituting NCS for
NBS and increasing the reaction temperature to 45 °C.11
Crucially, there was no evidence for premature cleavage of the
carbon−boron bond under these oxidative conditions.12
Condensation-Based Access to Boryl Thiazoles. The
synthesis of boryl heterocycles is commonly accomplished with
organometallic reagents under cryogenic conditions and is
effective for simple and/or highly biased heteroaromatic
substrates.13 Extension of this chemistry to functionally richer
molecules has been problematic due to functional group
tolerance and regioselectivity issues.14 To demonstrate the
utility of α-halogenated boryl aldehydes in the preparation of
borylated heterocycles, we set out to investigate the feasibility
of a one-pot aldehyde condensation/bromide displacement
annulation process.
Figure 2. Synthesis of 1 and quantitative formation of boryl-enamine
2.
Ozonolysis of allyl MIDA boronate on multigram scale
provided an efficient means for the preparation of the parent
α-boryl aldehyde 1, which was isolated as a white solid. With
this aldehyde in hand, we sought to investigate the formation of
α-boryl enamine 2 via condensation of α-boryl aldehyde 1 with
pyrrolidine. Pyrrolidine was selected for its nucleophilicity and
relatively unhindered nature compared to other aliphatic
amines.7 A condensation reaction between equimolar amounts
Thioamides are known to undergo annulation with α-
halogenated aldehydes.15 α-Bromo boryl aldehyde 3a was
subjected to cyclization conditions with a variety of primary
thioamides, which resulted in the corresponding 2,5-disub-
stituted boryl thiazoles as single regioisomers (Scheme 2, 13a−
1
of 1 and pyrrolidine in acetonitrile-d3 was monitored by H
NMR. Complete consumption of the aldehyde 1 was
accompanied by quantitative formation of the parent boryl
enamine 2 (>20:1 E:Z) within 5 min of mixing (Figure 2).8 It
was also found that 10 mol % pyrrolidine cleanly delivers a 9:1
aldehyde:enamine ratio in solution. This data led us to evaluate
the reactivity of boryl enamines as nucleophilic intermediates in
α-substitution chemistry, particularly in α-halogenation.9
We subjected the parent α-boryl aldehyde 1 to electrophilic
bromination conditions using N-bromosuccinimide (NBS) at
room temperature in the presence of 10 mol % pyrrolidine.
This resulted in the full consumption of the starting aldehyde
within 4 h; however, a mixture of mono- and dibrominated
species was obtained. Cooling the reaction mixture to 0 °C and
adding NBS slowly over 1 h afforded the monobrominated
boryl aldehyde in 67% yield (Scheme 1, 3a).10 The use of acetic
acid and water was found to be optimal for pyrrolidine turnover
and reduced reaction times.
Scheme 2. Condensation/Bromide Displacement with
Thioamides and Thioureas
Scheme 1. Substrate Scope of α-Boryl Aldehyde
Halogenation
c). Importantly, there was no evidence of premature C−B bond
scission under these conditions. Thioureas also participated in
the condensation reaction with 3a to produce a variety of 2-
amino-5-borylthiazoles in good yields (13d−g). The 2,5-series
of boryl thiazoles can now be accessed from 3a, whereas the
2,4-regioisomers can be obtained from our previously reported
α-bromo acyl boronate building blocks.6a A swap in the
oxidation states of adjacent carbons in these two building
blocks (bromo boryl aldehyde vs bromo acyl boronate)
provides the basis for regioselectivity.
We note that 2,5-disubstituted thiazoles are sporadically
utilized motifs in medicinal chemistry, despite the well-
recognized value of the thiazole core. This is evident upon
examination of the PDB database: only 7 crystallographically
characterized structures incorporate the 2,5-regioisomer hetero-
cycle motif, whereas 52 contain the 2,4-variant.16 We sought to
17670
dx.doi.org/10.1021/ja510963k | J. Am. Chem. Soc. 2014, 136, 17669−17673

Journal of the American Chemical Society
Article
demonstrate the application of our novel boryl thiazoles in
cross-coupling reactions. After an extensive screen of
conditions, we found that the use of Lipshutz’s surfactant
TPGS-750-M in water was essential in the SMCC trans-
formation (Scheme 3).17 Our condensation-driven access to the
In comparison to N-benzyl-N-propenyl benzamide, the boryl
enamide 14k possesses a relatively electron-rich α-carbon. In
addition, boron substitution results in enhanced electrophilicity
of the β-carbon as indicated by the 0.9 ppm downfield shift of
the Hb (1H NMR) signal relative to the reported alkyl
counterpart.23 The unusual electronic nature of boryl enamides
was confirmed using single crystal X-ray analysis of 14l (Figure
3). The enamide functionality features an abcd torsion angle of
Scheme 3. SMCC of 2,5-Disubstituted Boryl Thiazoles
2,5-disubstituted boryl thiazole core and successful SMCC of
13d extends the repertoire of options for medicinal chemistry18
and materials science.19
Mitigation of C → N Boryl Migration Captures Novel
Boryl Enamides and Enables Their Application in the
Synthesis of Heterocycles. The condensative synthesis of
boryl thiazoles proceeds through an equilibrating N-acyl imine/
enamide intermediate. Involvement of the enamide component
encouraged us to investigate boron’s influence on the enamide
functionality, in particular on the attenuation of nitrogen’s
nucleophilicity using boron substitution. This led us to pursue
the preparation of α-boryl enamide scaffolds for downstream
applications toward nitrogen-containing heterocycles.20 We
previously established that the addition of primary amines to α-
boryl aldehydes triggered C → N migration of the B[MIDA]
group, affording the undesired N-boryl enamines.21 Fortu-
nately, we have now identified a way to prevent this migratory
process and trap the C-boryl enamine species using acyl
chlorides. Thus, in the presence of Et3N and DMAP, we were
able to isolate the corresponding C-boryl enamides as white
solids after purification (Scheme 4) with no evidence of
rearrangement.22
Figure 3. X-ray structure of 14l. Hydrogen atoms are omitted for
clarity. Inset: zoom-in of enamide geometry.
127.7°, which stands in contrast to the value of 180°, typically
seen in other crystal structures of enamides.24 The atypical
torsion angle recorded for 14l results in the electronic isolation
of both amide and alkene functional groups. We became
interested in exploring the polarized electronic character of α-
boryl enamides in intramolecular transformations with the goal
of gaining access to a range of nitrogen-containing heterocycles.
We note that β-metalloenamides have been used or implicated
in synthesis only on a few occasions.25
To probe the possibility of α-boryl enamide cyclization, we
turned to the Heck reaction as electron-rich alkene substrates
are known to facilitate the migratory insertion process.26 When
14a was subjected to Heck reaction conditions with Pd(PPh3)4,
exclusive formation of the 3-methyleneisoindolone derived
from a 5-exo-trig cyclization was observed.27 The product was
formed as a mixture of E/Z alkene isomers (Scheme 5, 15k). A
Scheme 4. Trapping of α-Boryl Enamine Intermediates with
Acyl Chlorides Affords α-Boryl Enamides
Scheme 5. Borylmethyl-Isoindolones via 5-exo-trig
Cyclization of α-Boryl Enamides
17671
dx.doi.org/10.1021/ja510963k | J. Am. Chem. Soc. 2014, 136, 17669−17673

Journal of the American Chemical Society
Article
number of other boryl enamides were subjected to cyclization
conditions, delivering similar results. As a consequence of the
regioselective migratory insertion, the PdII-center attached to
the α-carbon forms the gem-bis-metallo sp3B−C−Pd inter-
mediate 16. The electron-rich sp3-boronate is proposed to
destabilize 16 due to the lack of Pd/boron interaction, thereby
promoting rapid β-hydride elimination. This stands in contrast
to reports by Hall28 and Shibata29 where no β-hydride
elimination with sp2B−C−Pd intermediates was observed in
the SMCC of 1,1-diborylalkanes and aryl halides. The crude
methyleneisoindolones were then subjected to hydrogenation
in the presence of Pd/C to afford the novel borylmethyl-
isoindolones after column chromatography.30 This sequence
not only demonstrates the relative stability of the C−B bond
under our conditions, but also suggests the downstream
potential for asymmetric hydrogenation to access enantioen-
riched borylmethyl-isoindolones.
We are interested in the synthetic transformation of the
sp3C−B bond of borylmethyl-isoindolones 15a−g through
SMCC.31 A comprehensive literature search revealed only two
examples of 6-membered ring synthesis32 via intramolecular
SMCC of alkyl boronates and no examples of 7-membered ring
formation.33 This lack of precedent for the intramolecular
SMCC of sp3C−B bonds can be attributed to the challenges
associated with transmetalation to form the medium ring
palladacycles. Fortunately, alkyl-MIDA boronates 15a−g were
readily converted into the corresponding tetracyclic lactams
17a−g in good yields (Scheme 6), which exemplifies the utility
migration. Heck cyclization of the enamides provides the
privileged isoindolone scaffold equipped with boron. The
stability to reductive conditions suggests that borylated
enamides may find utility in asymmetric hydrogenation. The
application of the Heck products through SMCC engagement
of the C−B bond enables convenient access to biologically
relevant tetracyclic scaffolds and affords novel retrosynthetic
opportunities for the construction of polycyclic scaffolds.
Overall, our chemistry realizes the synthetic potential of α-
boryl enamine and α-boryl enamide linchpins for production of
nitrogen heterocycles and offers a rich repertoire of tools for
the construction of heterocycles through the use of
intermediates containing B−C−C−N linkages.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed procedures, spectral data (1H, 13C, 11B NMR and
HRMS) for all new compounds and X-ray data tables are
available on the Internet. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
ayudin@chem.utoronto.ca
■
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
Scheme 6. Intramolecular SMCC Process
ACKNOWLEDGMENTS
■
We would like to thank NSERC for funding this project
through an operating grant. J.S.D. would like to thank NSERC
for PGS-D and OGS for QEII-funding. A.Z. would like to thank
NSERC for CGS-M funding. We would also like to thank Dr.
Alan Lough for X-ray structure determination of 14l, E-15a and
17g.
REFERENCES
■
(1) (a) Afagh, N. A.; Yudin, A. K. Angew. Chem., Int. Ed. 2010, 49,
262−310. (b) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193−205.
(2) (a) He, Z.; Yudin, A. K. J. Am. Chem. Soc. 2011, 133, 13770−
13773. (b) Li, J.; Burke, M. D. J. Am. Chem. Soc. 2011, 133, 13774−
13777.
(3) (a) He, Z.; Zajdlik, A.; Yudin, A. K. Acc. Chem. Res. 2014, 47,
1029−1040. (b) He, Z.; Zajdlik, A.; Yudin, A. K. Dalton Trans. 2014,
43, 11434−11451.
(4) He, Z.; Zajdlik, A.; St. Denis, J. D.; Assem, N.; Yudin, A. K. J. Am.
Chem. Soc. 2012, 134, 9926−9929.
(5) (a) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716−
6717. (b) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc.
2009, 131, 6961−6963. (c) Dick, G. R.; Woerly, E. M.; Burke, M. D.
Angew. Chem., Int. Ed. 2012, 51, 2667−2672.
(6) (a) He, Z.; Trinchera, P.; Adachi, S.; St. Denis, J. D.; Yudin, A. K.
Angew. Chem., Int. Ed. 2012, 51, 11092−11096. (b) St. Denis, J. D.;
He, Z.; Yudin, A. K. Org. Biomol. Chem. 2012, 10, 7900−7902.
(7) Stork, G.; Brizzolara, A.; Landeman, H.; Szmuszkovicz, J.; Terrell,
R. J. Am. Chem. Soc. 1963, 85, 207−222.
(8) Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2004, 43, 6722−6724.
(9) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471−5569.
(10) The original report on the amine-catalyzed bromination of
aldehydes: Bertelsen, S.; Halland, N.; Bachmann, S.; Marigo, M.;
Braunton, A.; Jørgensen, K. A. Chem. Commun. 2005, 4821−4823.
of SMCC for the formation of 6- and 7-membered rings. This
cyclization protocol enables access to the biologically relevant
class of tetracyclic scaffolds seen in natural products such as
lennoxamine.34
SUMMARY
■
In summary, we have explored the B−C−C−N motifs in the
synthesis of nitrogen-containing heterocycles. Mild α-halogen-
ation, catalyzed by pyrrolidine, proceeds through the
intermediacy of boryl enamines. The halogenated products
can be used in the regioselective synthesis of a new class of 2,5-
disubstituted boryl thiazoles. α-Boryl aldehydes also undergo
quantitative condensation/amidation sequence, which affords
stable α-boryl enamides without concomitant C → N
17672
dx.doi.org/10.1021/ja510963k | J. Am. Chem. Soc. 2014, 136, 17669−17673

Journal of the American Chemical Society
Article
(11) The use of 50 mol % L-proline in place of 10 mol % pyrrolidine
for the chlorination of α-MIDA boryl phenyl acetaldehyde (8b) results
in a 49% enantioinduction.
12180−12182. (b) Molander, G. A.; Wisniewski, S. R. J. Am. Chem.
Soc. 2012, 134, 16856−16868.
(33) The formation of six-membered rings has been documented in
palladium-catalyzed C−H arylation, but only when the reductively
eliminated C−C bond was between an aryl and cyclopropyl carbon
atoms: (a) Saget, T.; Cramer, N. Angew. Chem., Int. Ed. 2012, 51,
12842−12845. (b) Saget, T.; Perez, D.; Cramer, N. Org. Lett. 2013, 15,
1354−1357.
(12) Examples of oxidative halo-deborylation: (a) Petasis, N.; Yudin,
A. K.; Zavialov, I. A.; Prakash, G. K. S.; Olah, G. A. Synlett 1997, 606−
608. (b) Wu, H.; Hynes, J., Jr. Org. Lett. 2010, 12, 1192−1195.
(13) Hall, D. G. Structure, Properties, and Preparation of Boronic
Acid Derivatives. Overview of Their Reactions and Applications. In
Boronic Acids: Preparation and Applications in Organic Synthesis
Medicine and Materials.; Hall, D. G., Ed.; Wiley-VCH, Weinheim,
Germany, 2005; pp 28−57.
(34) (a) Kise, N.; Isemoto, S.; Sakurai, T. J. Org. Chem. 2011, 76,
9856−9860. (b) Zhang, W.; Pugh, G. Tetrahedron Lett. 1999, 40,
7591−7594. (c) Couty, S.; Meyer, C.; Cossy, J. Tetrahedron Lett. 2006,
47, 767−769.
(14) Directed metalation of aryl substrates: Snieckus, V. Chem. Rev.
1990, 90, 879−933.
(15) Britton, R.; Kang, B. Nat. Prod. Rep. 2013, 30, 227−236.
(16) A single example of MIDA thiazol-5-ylboronate has been
reported: Dick, G. R.; Knapp, D. M.; Gillis, E. P.; Burke, M. D. Org.
Lett. 2010, 12, 2314−2317.
(17) TPGS-750-M as an enabling surfactant in difficult cross-
coupling reactions: (a) Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser,
R.; Nishikata, T.; Duplais, C.; Krasovskiy, A.; Gaston, R. D.; Gadwood,
R. C. J. Org. Chem. 2011, 76, 4379−4391. (b) Isley, N. A.; Gallou, F.;
Lipshutz, B. H. J. Am. Chem. Soc. 2013, 135, 17707−17710.
(18) Recent examples of the synthesis of thiazolylboronic esters:
(a) Lohrey, L.; Uehara, T. N.; Tani, S.; Yamaguchi, J.; Humpf, H.-U.;
Itami, K. Eur.J. Org. Chem. 2014, 3387−3394. (b) Schnurch, M.;
̈
Hammerle, J.; Mihovilovic, M. D.; Stanetty, P. Synthesis 2010, 837−
̈
843.
(19) Review of thiazole-containing organic semiconductors: Lin, Y.;
Fan, H.; Li, Y.; Zhan, X. Adv. Mater. 2012, 24, 3087−3106.
(20) Reviews of enamide chemistry: (a) Carbery, D. R. Org. Biomol.
Chem. 2008, 6, 3455−3460. (b) Gigant, N.; Chausset-Boissarie, L.;
Gillaizeau, I. Chem.Eur. J. 2014, 20, 7548−7564.
(21) The use of tosyl amine, benzylamine, or aniline results in a
quantitative C → N migration of the B[MIDA] group, which is
surprising given the stability of α-boryl aldehydes. Details pertaining to
these results are found in reference 2a.
(22) A single example of α-boryl enecarbamate has been reported:
Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.; Singleton, D. A.;
Maleczka, R. E., Jr.; Smith, M. R., III. J. Am. Chem. Soc. 2012, 134,
11350−11353.
(23) Alkyl-enamide 1H NMR (C6D6): αC-H 4.84 ppm Neugnot, B.;
Cintrat, J.-C.; Rousseau, B. Tetrahedron 2004, 60, 3575−3579.
(24) X-ray structure of a non-borylated enamide: Ghosh, S.; Uckun,
F. M. Acta Crystallogr. Sect. C 1999, 55, 1364−1365.
(25) Examples of β-metalloenamides in synthesis: (a) Prasad, A. B.
Bhanu; Knochel, P. Tetrahedron 1997, 53, 16711−16720. (b) Yasui,
H.; Yorimitsu, H.; Oshima, K. Bull. Chem. Soc. Jpn. 2008, 81, 373−379.
(c) Witulski, B.; Buschmann, N.; Bergstraßer, U. Tetrahedron 2000, 56,
̈
8473−8480.
(26) Reviews of the Heck reaction: (a) Beletskaya, I. P.; Cheprakov,
A. V. Chem. Rev. 2000, 100, 3009−3066. (b) Ruan, J.; Xiao, J. Acc.
Chem. Res. 2011, 44, 614−626.
(27) Examples of 5-exo-trig cyclization of enamides: (a) García, A.;
́
Rodríguez, D.; Castedo, L.; Saa, C.; Dominguez, D. Tetrahedron Lett.
2001, 42, 1903−1905. (b) Wada, Y.; Nishida, N.; Kurono, N.;
Ohkuma, T.; Orito, K. Eur. J. Org. Chem. 2007, 4320−4327.
(28) Lee, J. C. H.; McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3,
894−899.
(29) Endo, K.; Ohkubo, T.; Hirokami, M.; Shibata, T. J. Am. Chem.
Soc. 2010, 132, 11033−11035.
(30) Batracylin, a DNA topoisomerase inhibitor that contains the
isoindolone core: Rao, V. A.; Agama, K.; Holbeck, S.; Pommier, Y.
Cancer Res. 2007, 67, 9971−9979.
(31) (a) St. Denis, J. D.; Scully, C. C. G.; Lee, C. F.; Yudin, A. K. Org.
Lett. 2014, 16, 1338−1341. (b) Lee, S. J.; Gray, K. C.; Paek, J. S.;
Burke, M. D. J. Am. Chem. Soc. 2008, 130, 466−468.
(32) (a) Smith, S. M.; Hoang, G. L.; Pal, R.; Bani Khaled, M. O.;
Pelter, L. S. W.; Zeng, X. C.; Takacs, J. M. Chem. Commun. 2012, 48,
17673
dx.doi.org/10.1021/ja510963k | J. Am. Chem. Soc. 2014, 136, 17669−17673