Trapping rhodium vinylcarbenoids with aminochalcones for the synthesis of medium-sized azacycles

Article abstract of DOI:10.1016/j.tetlet.2019.151253

A rhodium carbenoid initiated cascade has been developed for the stereoselective synthesis of medium-sized azacycles. The cascade approach utilizes readily accessible N-benzyl protected aminochalcones and vinyldiazo compounds to access 9-membered azacycle

Full text of DOI:10.1016/j.tetlet.2019.151253

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Trapping Rhodium Vinylcarbenoids with Aminochalcones for the Synthesis of
Medium-Sized Azacycles
Kiran Chinthapally, Nicholas P. Massaro, Sabrina Ton, Eric D. Gardner,
Indrajeet Sharma
PII:
S0040-4039(19)31033-0
DOI:
https://doi.org/10.1016/j.tetlet.2019.151253
TETL 151253
Reference:
Tetrahedron Letters
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Accepted Date:
23 July 2019
26 September 2019
2 October 2019
Please cite this article as: Chinthapally, K., Massaro, N.P., Ton, S., Gardner, E.D., Sharma, I., Trapping Rhodium
Vinylcarbenoids with Aminochalcones for the Synthesis of Medium-Sized Azacycles, Tetrahedron Letters (2019),
doi: https://doi.org/10.1016/j.tetlet.2019.151253
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Trapping Rhodium Vinylcarbenoid with
Aminochalcones for the Synthesis of
Medium-Sized Azacycles
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Kiran Chinthapally, Nicholas P. Massaro, Sabrina Ton, Eric D. Gardner, and Indrajeet Sharma*
O
O
Rh2(OAc)4
(1 mol %)
R1
R1
R
R
Bn
N
N
H
toluene, reflux
+
Bn
R2O
N2
R2O
9 examples
O
56 83%

only Z-isomer
O

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Trapping Rhodium Vinylcarbenoids with Aminochalcones for the Synthesis of
Medium-Sized Azacycles
Kiran Chinthapally, Nicholas P. Massaro, Sabrina Ton, Eric D. Gardner, and Indrajeet Sharma*
Department of Chemistry and Biochemistry, and Institute of Natural Products Applications and Research Technologies, University of Oklahoma, 101 Stephenson
Parkway, Norman, OK-73071 (USA)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A rhodium carbenoid initiated cascade has been developed for the stereoselective synthesis of
medium-sized azacycles. The cascade approach utilizes readily accessible N-benzyl protected
aminochalcones and vinyldiazo compounds to access 9-membered azacycles through a carbene-
nitrogen insertion/aldol/oxy-Cope sequence. The cascade reaction has proven general with a
range of N-benzyl protected aminochalcones and vinyldiazos to provide diverse medium-sized
azacycles.
Available online
Keywords:
Diazo Compounds
Rhodium Carbenoids
Medium-sized Rings
Azacycles
2009 Elsevier Ltd. All rights reserved.
1. Introduction
intermediate, which undergoes an oxy-Cope rearrangement to
provide 9-membered oxacycles. We also extended this cascade
Medium-sized (8-12-membered) heterocycles are commonly
found in bioactive natural products and cyclic peptides.[1] The
cyclic constraints within these molecules leads to improved
binding affinity compared to their linear counterparts.[2]
Furthermore, medium-sized heterocycles often exhibit improved
pharmacokinetics due to their larger ring sizes and
conformational constraints.[3] Still, medium-sized rings remain
underrepresented among approved pharmaceuticals compared to
their smaller-sized ring (4-7 membered) counterparts.[4]
reaction to the synthesis of corresponding medium-sized
lactones.[11b]
Building upon these findings, we envision extending the
carbene cascade approach to the synthesis of 9-membered
azacycles, which are found in a variety of natural products,
medicinally relevant compounds, and drug molecules (Figure
2)[12]
a) alkene metathesis
R
R
R
The lack of prevalence in drug molecules could be attributed
to the challenges associated with the synthesis of medium-sized
rings.[5] Many of the methods for constructing medium-sized
rings rely on intramolecular cyclization strategies, which often
pose challenges due to the entropic and enthalpy barriers, and
also require high dilution conditions to reduce polymerization.[6]
Although, there are other methods such as olefin metathesis [7a]
and transition metal coupling reactions [7b] for the synthesis of
these scaffolds, they often require conformational constraint to
promote cyclization (Figure 1a, 1b).[8] Ring expansion reactions
that are insensitive to substrate conformational effects provide an
alternative to conventional cyclization approaches.[9] However,
construction of an appropriate precursor for a ring expansion
reaction often requires multiple steps, and limits the synthetic
utility (Figure 1c, 1d).[10]
R
Hoveyda-Grubbs 2
Aubé, 2009 [7a]
N
N
Ts
R
Ts
b) Coupling
Cu(OTf)2, 2,6-lutidine
4:1 CH2Cl2:HFIP
O
SnBu3
O
NH
N
Bode, 2014 [7b]
3
R
c) Rearrangement
X
X
R1
R1
LDA, THF
NH
N
Clayden, 2016 [9a-b]
N
R2
O
Ar
Ar
N
O
R2
d) Ring Expansion
O
O
O
To overcome this synthetic challenge, we recently reported a
rhodium carbenoid initiated convergent cascade approach, which
provides access to the functionalized medium-sized oxacycles
with high stereoselectivity.[11a] The cascade reaction begins
with carbene-oxygen insertion followed by an intramolecular
Bn
N
DBU, CH2Cl2
Fmoc
N
N
Unsworth, 2017 [9c]
Bn
N
H
O
Figure 1. Previous synthetic approaches towards nine-membered azacycles
aldol cyclization to provide
a substituted tetrahydrofuran

2
HO
Table 1. Catalyst screening for the formation of azacycle 3a
O
O
N
OH
NH
O
Ph
H
N
N
N2
Ph
+
Conditionsa
N
N
Bn
BnO
Bn
H
N
BnO
2a
O
MeO2C
H
1a
3a
N
MeO
N
OAc
CO2Me
O
H
HO
vinblastine
anticancer
()-indolactam V
PKC activator
Entry
1
Catalyst
Rh2(esp)2
Mol (%), t
Yield (%)b
38
1.0, 3 h
1.0, 3 h
1.0, 3 h
1.0, 3 h
O
N
2
3
4
Rh2(OAc)4
Rh2(TPAc)4
Rh2(TFAd)4
67
NR
10
N
O
N
H
aAll optimization reactions were performed by adding a 0.45 M solution of 2a
(2.0 equiv) into a 0.1 M solution of 1a (1.0 equiv) with catalysts via a syringe
pump over 2.5 h, after the addition of diazo, all reaction were refluxed for an
additional 30 min. bIsolated yields after column chromatography. cTPA =
triphenylacetate; dTFA = trifluoroacetate; NR = no reaction.
N
H
(-)-rhazinicine
anticancer
quebrachamine
adrenergic blocking activity
Figure 2. Nine-membered azacycle natural products
With conditions in hand, we then investigated the scope of this
cascade sequence using Rh2(OAc)4 as a catalyst (Figure 3). Using
vinyldiazo 2a as a standard substrate, the scope of N-benzyl
protected aminochalcones was explored and found to be broad,
encompassing a range of electron-rich and electron-deficient
substituents on the aromatic side chain of N-benzyl protected
aminochalcones.
For the initial optimization to access 9-membered azacycles,
aminochalcone S1a and vinyldiazo 2a were selected as model
substrates. The syringe pump addition of vinyldiazo 2a to 2’-
aminochalcone S1a in the presence of Rh2(esp)2 in refluxing
toluene provided a major product, in which the characteristic
enamine proton in 1H-NMR, and ketone peak in 13C-NMR
spectrum were missing. Further structural analyses suggested the
formation of an unexpected quinoline scaffold 4 (Scheme 1).[13]
O
O
R1
Rh2(OAc)4
R
O
R1
+
(1 mol %)
Ph
N2
N
R
Rh2(esp)2
(1 mol %)
Bn
Ph
Bn
R2O
N
toluene, reflux
+
H
R2O
O
NH2 N2
S1a
1
2
3
O
OBn
toluene, reflux
N
Cl
OMe
BnO
O
O
4
, 61%
2a
O
O
O
observed
Ph
aldol
condensation
N
N
N
Bn
BnO
Bn
BnO
Bn
BnO
O
Ph
Ph
O
O
O
HO
3a
3b
3c
, 67%
, 69%
, 75%
O
NH
O
CN
N
BnO
H
O
N
O
OBn
O
Ph
Br
Ph
Ph
expected
N
N
Bn
BnO
Bn
BnO
Bn
BnO
Scheme 1. Rhodium carbenoid initiated unexpected cascade leading to the
formation of tricyclic quinoline 4
O
O
O
3d
3e
3f
, 78%
Mechanistic analyses revealed that the quinoline forms from
the corresponding azacycles via an aldol type condensation due
to the driving force of aromatization.[13] Inspiring from these
results, we thought of stopping the cascade at the azacycle stage
using N-benzyl protected aminochalcones.
, 56%
O
, 71%
O
Ph
O
N
Br
Ph
Ph
Ph
N
N
Bn
BnO
Bn
O
O
Bn
O
Cl3C
O
O
2. Results and discussion
3g
3h
3i
, 83%
, 80%
, 74%
For the initial catalyst screening, N-benzyl protected
aminochalcone 1a and vinyl diazo benzoate 2a were selected as
model substrates and exposed to Rh2(esp)2 in toluene (boiling
point 110 °C) at reflux, which obtained the desired 9-membered
azacycle 3a, albeit in low conversion (Table 1, entry 1).
Encouraged by this result, we screened other rhodium
carboxylates catalysts to improve the yield of the transformation
(Table 1, entries 2−5). Among them, Rh2(OAc)4 was found to be
the most efficient catalyst for the cascade sequence and provided
the corresponding nine-membered azacycle 3a (entry 2).
Figure 3. Scope of Rh2(OAc)4-catalyzed cascade for the synthesis of
functionalized quinolines; all reactions were performed by adding a 0.45 M
solution of 2 (2.0 equiv) into a 0.1 M solution of 1 (1.0 equiv) over 2.5 h via a
syringe pump; after the addition of diazo compound, all reactions were
refluxed for an additional 30 min.
In the case of electron-rich (3b) and neutral (3c) substituents
worked very well, but a cyano- substituted aromatic side chain of
N-benzyl protected aminochalcone resulted in a low yield (3d).
We were pleased to find that the cascade sequence tolerated
equally well the substitution at the aniline ring of N-benzyl
protected aminochalcones (Figure 3, 3e–3g). We did not observe
any major side products resulting from alkyne functionality (3g,

3
3h), which has the propensity to undergo cyclopropenation,[14]
as well as carbene-alkyne metathesis[15] with rhodium
carbenoids. The structure of the compound 3g was further
confirmed by the single crystal X-ray structure and the geometry
of the double bond is found to be Z-isomer (Figure 4).[16a]
Finally, the cascade was attempted with vinyldiazo 2c bearing a
trichloroethyl ester side-chain. To our delight, the cascade
proceeded in high yield to provide azacycle scaffold 3i.
Moreover, the structure of the compound 3i was also confirmed
by the single crystal X-ray structure (Figure 4).[16b]
starting materials to provide functionalized azacycles. An
important feature of this transformation is its high chemo- and
regio-selectivity. Furthermore, the straightforward synthesis of
medium-sized azacycles would allow exploration of this less-
charted area of chemical space, which is currently occupied with
heterocycles having small (4-7 atoms) rings and macrocycles.
Acknowledgments
We thank Dr. Susan Nimmo, Dr. Steven Foster, and Dr. Douglas
R. Powell from the Research Support Services, University of
Oklahoma, for expert NMR, mass spectral, and X-ray
crystallographic analyses respectively. The work was supported
by NSF CHE-1753187, and American Chemical Society
Petroleum Research Fund (ACS-PRF) Doctoral New Investigator
grant (PRF no. 58487-DNI1).
Ph
O
O
Ph
Ph
N
N
Bn
BnO
Bn
O
Cl3C
O
O
3g
3i
References and notes
[1] (a) A. Hussain, S. K. Yousuf, D. Mukherjee, RSC Adv. 4 (2014)
43241–43257; (b) X.-M. Zhang, Y.-Q. Tu, F.-M. Zhang, H. Shao,
X. Meng, Angew. Chem. Int. Ed. 50 (2011) 3916–3919; (c) B. M.
Trost, A. C. Burns, M. J. Bartlett, T. Tautz, A. H. Weiss, J. Am.
Chem. Soc. 134 (2012) 1474–1477; (d) Y. Kasai, N. Michihata, H.
Nishimura, T. Hirokane, H. Yamada, Angew. Chem. Int. Ed. 51
(2012) 8026–8029; (e) A. Frichert, P. G. Jones, T. Lindel, Angew.
Chem. Int. Ed. 55 (2016) 2916–2919; (f) F.-X. Wang, J.-Y. Du,
H.-B. Wang, P.-L. Zhang, G.-B. Zhang, K.-Y. Yu, X.-Z. Zhang,
X.-T. An, Y.-X. Cao, C.-A. Fan, J. Am. Chem. Soc. 139 (2017)
4282–4285; (g) R. Mendoza-Sanchez, V. B. Corless, Q. N. N.
Nguyen, M. Bergeron-Brlek, J. Frost, S. Adachi, D. J. Tantillo, A.
K. Yudin, Chem. Eur. J. 23 (2017) 13319–13322.
[2] A. R. Khan, J. C. Parrish, M. E. Fraser, W. W. Smith, P. A.
Bartlett, and M. N. G. James. Biochemistry 37 (1998) 16839–
16845.
[3] (a) Y.-U. Kwon, T. Kodadek, Chemistry & Biology 14 (2007)
671–677; (b) T. Rezai, B. Yu, G. L. Millhauser, M. P. Jacobson,
R. S. Lokey, J. Am. Chem. Soc. 128 (2006) 2510–2511.
Figure 4. X-ray crystal structure of azacycle 3g and 3i
The reaction pathway for the synthesis of azacycles can be
plausibly rationalized by the following mechansim (Scheme
2).[13] First, vinyldiazo 2 is decomposed by the dirhodium
carboxylate to form a rhodium vinylcarbenoid that undergoes a
chemoselective nitrogen insertion/aldol cyclization to provide
indoline 4.[17a] The indoline intermediate 4 sets the stage for a
thermally driven concerted oxy-Cope rearrangement, which
results in an enol-form. The enol-form then rearranges to the
thermodynamically more stable keto-form 3. Moreover, the
formation of Z-isomer could be explained based on the boat
transition state of the cycloadduct intermediate. In addition to this
proposed mechanism, it is also plausible that the reaction
proceeds through a metal dissociated ammonium ylide trapping
mechanism.[17b]
[4] E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 57 (2014)
10257–10274.
[5] Y. Choi, H. Kim, S. B. Park, Chem. Sci. 10 (2019) 569–575.
[6] For reviews on medium-sized rings, see: (a) G. Illuminati, L.
Mandolini, Acc. Chem. Res. 14 (1981) 95–102; (b) L. Yet, Chem.
Rev. 100 (2000) 2963–3007; (c) K. C. Majumdar, RSC Adv. 1
(2011) 1152–1170; (d) A. Sharma, P. Appukkuttan, E. Van der
Eycken, Chem. Commun. 48 (2012) 1623–1637. Synthesis of
medium sized azacycles through linear precursor, see: (e) J. E.
Hall, J. V. Matlock, J. W. Ward, K. V. Gray, J. Clayden, Angew.
Chem., Int. Ed. 55 (2016) 11153–11157; (f) R. W. Shaw, T.
Gallagher, J. Chem. Soc., Perkin Trans. 1 (1994) 3549–3555; (g)
T. M. A. Barlow, M. Jida, K. Guillemyn, D. Tourwe, V. Caveliers,
S. Ballet, Org. Biomol. Chem. 14 (2016) 4669–4677; (h) Z. Li, A.
Kumar, D. D. Vachhani, S. K. Sharma, V. S. Parmar, E. V. Van
der Eycken, Eur. J. Org. Chem. (2014) 2084–2091; (i) K. C.
Majumdar, K. Ray, S. Ganai, Tetrahedron Lett. 51 (2010) 1736–
1738; (j) B. A. Aderibigbe, I. R. Green, T. Mabank, M. Janse van
Rensburg, G. L. Morgans, M. A. Fernandes, J. P. Michael, W. A.
L. van Otterlo, Tetrahedron 73 (2017) 4671–4683; (k) L.-C. Yang,
Z.-Q. Rong, Y.-N. Wang, Z. Y. Tan, M. Wang, Y. Zhao, Angew.
Chem., Int. Ed. 56 (2017) 2927–2931.
[7] (a) M. Szostak, J. Aubé, Org. Lett. 11 (2009) 3878–3881 (b) C.-V.
T. Vo, M. U. Luescher, J. W. Bode, Nat. Chem. 6 (2014) 310–
314.
[8] A. Deiters, S. F. Martin, Chem. Rev. 104 (2004) 2199–2238.
[9] (a) J. E. Hall, J. V. Matlock, J. W. Ward, K. V. Gray, J. Clayden,
Angew. Chem. Int. Ed. 55 (2016) 11153–11157; (b) J. E. Hill, J.
V. Matlock, Q. Lefebvre, K. G. Cooper, J. Clayden. Angew.
Chem. Int. Ed. 57 (2018) 5788–5791; (c) T. C. Stephens, M. Lodi,
A. M. Steer, Y. Lin, M. T. Gill, W. P. Unsworth, Chem. Eur. J. 23
(2017) 13314–13318.
R2
N2
HO
2
Rh2L4
R3O
N2
O
R
R
OR3
N
R1
O
4
O
R2
Rh2L4
R2
L4Rh2
R3O
R
HO
N
N–H
insertion
H
R1
O
OR3
O
OR3
N
O
1O
R
R2
O
R
oxy-Cope
R1
N
H
1
R2
R2
OH
Keto-enol
R
R
N
N
R1
OR3
3
OR3
R1
O
O
Scheme 2. Plausible reaction mechanism for the synthesis of azacycles
[10] Synthesis of medium-sized azacycles through ring expansion, see:
(a) C. Kitsiou, J. J. Hindes, P. I'Anson, P. Jackson, T. C. Wilson,
E. K. Daly, H. R. Felstead, P. Hearnshaw, W. P. Unsworth,
Angew. Chem., Int. Ed. 2015, 54, 15794–15798; (b) A. Klapars,
S. Parris, K. W. Anderson, S. L. Buchwald, J. Am. Chem. Soc.
3. Conclusion
In summary, the reported rhodium carbenoid initiated cascade
approach is convergent in nature and uses readily accessible

4
2004, 126, 3529–3533; (c) W. Zhao, H. Qian, Z. Li, J. Sun,
Angew. Chem., Int. Ed. 2015, 54, 10005–10008.
[11] (a) K. Chinthapally, N. P. Massaro, I. Sharma, Org. Lett. 18
(2016) 6340–6343; (b) N. P. Massaro, J. C. Stevens, A. Chatterji,
I. Sharma, Org. Lett. 20 (2018) 7585−7589.
[12] (a) Y. Endo, K. Shudo, A. Itai, M. Hasegawa, S. Sakai,
Tetrahedron, 42 (1986) 5905−5924; (b) I. Gerasimenko, Y.
Sheludko, J. Stöckigt, J. Nat. Prod. 64 (2001) 114−116; (c) B.
Gigant, C. Wang, R. B. G. Ravelli, F. Roussi, M. O. Steinmetz, P.
A. Curmi, A. Sobel, M. Knossow, Nature 435 (2005) 519−522; (d)
H. F. Deutsch, M. A. Evenson, P. Drescher, C. Sparwasser, P. O.
Madsen, J Pharm Biomed Anal 12 (1994) 1283−1287.
[13] K. Chinthapally, N. P. Massaro, H. L. Padgett, I. Sharma, Chem.
Commun., 53 (2017) 12205−12208.
[14] T. Goto, K. Takeda, N. Shimada, H. Nambu, M. Anada, M. Shiro,
K. Ando, S.-I. Hashimoto, Angew. Chem., Int. Ed. 50 (2011)
6803–6808.
[15] (a) Y. Zheng, J. Mao, Y. Weng, X. Zhang, X. Xu, Org. Lett. 17
(2015) 5638–5641; (b) H. Qiu, Y. Deng, K. O. Marichev, M. P.
Doyle, J. Org. Chem. 82 (2017) 1584–1590; (c) S. Jansone-
Popova, J. A. May, J. Am. Chem. Soc. 134 (2012) 17877–17880.
[16] (a) 3g CCDC 1887929; (b) 3i CCDC 1887930.
[17] (a) S. M. Nicolle, W. Lewis, C. J. Hayes, C. J. Moody, Angew.
Chem. Int. Ed. 55 (2016) 3749–3753; (b) X. Guo, Y. Yue, G. Hu,
J. Zhou, Y. Zhao, L. Yang, W. Hu, Synlett, 13 (2009) 2109–2114.
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
A
convergent approach to 9-membered
azacycles is described.
 The rhodium carbene initiated three step cascade
utilizes readily accessible starting materials.
 The cascade reaction accommodates a variety of
functional groups.
 The reaction provides high chemo- and regio-
selectivity affording only z-isomer azacycles.