Tandem homologation-acylation chemistry: Single and double homologation

Article abstract of DOI:10.1016/j.tet.2021.132223

Treatment of β-dicarbonyls with the Furakawa-variant of the Simmons-Smith reagent results in homologation and production of an intermediate zinc enolate. Treatment of the enolate with various acylating agents generate products with both γ-dicarbonyl funct

Full text of DOI:10.1016/j.tet.2021.132223

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem homologation-acylation chemistry: Single and double
homologation
*
Carley S. Henderson, Jennifer R. Mazzone, Amanda M. Moore, Charles K. Zercher
Department of Chemistry, University of New Hampshire, Durham, NH, 03824, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 March 2021
Received in revised form
Treatment of
mologation and production of an intermediate zinc enolate. Treatment of the enolate with various
acylating agents generate products with both -dicarbonyl functionality and
In situ exposure of the acylated product to additional zinc carbenoid effects a second regiospecific ho-
mologation reaction.
b-dicarbonyls with the Furakawa-variant of the Simmons-Smith reagent results in ho-
g
b
Àdicarbonyl functionality.
4
May 2021
Accepted 7 May 2021
Available online xxx
©
2021 Elsevier Ltd. All rights reserved.
Keywords:
Zinc carbenoid
Homologation
Acylation
The generation of functionalized furans, pyrroles, and thio-
phenes has attracted significant interest due to the prevalence of
these heterocyclic ring systems in natural products and materials
science applications. Although all of these heterocycles can be
formed from 1,4-dicarbonyl compounds through application of the
Paal-Knorr synthesis [1e3], the challenges associated with pre-
paring highly functionalized 1,4-diketone starting materials have
impacted the broad application of this method of heterocycle for-
mation. Creative approaches based on the Stetter reaction [4],
conjugate additions [5], and transformation of furan systems [6]
have been developed to address this challenge, although there is
still a need in the synthetic community for new methods in 1,4-
diketone synthesis. Our interest in the development of tandem
reaction strategies based on a zinc carbenoid-mediated homolo-
gation reaction has led to the identification of a novel, practical
approach to functionalized 1,4-dicarbonyl systems.
position has been achieved by tandem reactions of zinc enolate 2
with a variety of electrophiles including carbenoids [12], halogens
[13], activated imines [14], aldehydes [15], and thioesters [16]
(Scheme 1).
Compounds obtained from tandem homologation reactions
have been shown to be appropriate substrates for a variety of
heterocycles through application of Paal-Knorr synthesis [16e18].
Oxidation of the tandem homologation-aldol products with PCC
provided the 1,4-dicarbonyls [16,17] used for Paal-Knorr synthesis
[18]. The use of thioesters to successfully trap the organometallic
intermediate (2) was reported as a direct method for the formation
of 1,4-dicarbonyls [16], although other acylating agents, like acid
chlorides and benzotriazole-activated acids, were not successful in
trapping the intermediate. The use of anhydrides was not discussed
in this report.
Recently our group reported the total synthesis of papyracillic
acid B and 4-epi-papyracillic acid C using the zinc-mediated ho-
mologation methodology [19]. These members of the papyracillic
acid family of natural products [20], which contains a spiro-fused
cyclic ketal core, were synthesized through the use of a tandem
homologation-acylation reaction. This key step constituted the first
reported example of an anhydride being used to trap reactive in-
termediate 2, so our success in trapping the organometallic inter-
mediate with anhydrides suggested an expanded investigation of
the process, with a goal of increased efficiency and the minimiza-
tion of byproduct formation.
Homologation of
b-keto esters to their g-keto counterparts
through the use of Furukawa-modified zinc carbenoid [7] was first
reported in 1997 [8]. Subsequently, the scope of this homologation
reaction has been expanded to include the use of other
substrates [9,10] and the ability to functionalize at both the
positions of the -keto product. Regioselective functionalization of
the -position has been achieved through the use of substituted
zinc carbenoids [11], while regioselective functionalization of the
b
-keto
a
and
b-
g
b
a
-
An investigation of a general homologation/acylation strategy
revealed that optimization of stoichiometry was key to the
*
Corresponding author.
E-mail address: chuck.zercher@unh.edu (C.K. Zercher).
https://doi.org/10.1016/j.tet.2021.132223
040-4020/© 2021 Elsevier Ltd. All rights reserved.
0
Please cite this article as: C.S. Henderson, J.R. Mazzone, A.M. Moore et al., Tandem homologation-acylation chemistry: Single and double
homologation, Tetrahedron, https://doi.org/10.1016/j.tet.2021.132223

C.S. Henderson, J.R. Mazzone, A.M. Moore et al.
Tetrahedron xxx (xxxx) xxx
Scheme 1. Tandem Chain Extension Chemistry.
minimization of byproducts formed in the tandem reaction
Table 1). For example, treatment of methyl pivaloylacetate (4) with
three equivalents of carbenoid followed by the addition of acetic
anhydride led to the formation of three main products: -keto ester
, the desired acylated product (7), as well as a homologue of the
acylation product (8). It was hypothesized that this result arises
from the formation of a new -keto ester (7), which introduces an
quenched before acylation took place. Conversely, treatment of
methyl pivaloylacetate with four equiv of carbenoid followed by the
addition of acetic anhydride (Table 1, entry 3) demonstrated that it
is possible to bias the reaction towards the formation of compound
8.
The order of addition involving acetic anhydride was crucial to
efficient homologation-acylation. When acetic anhydride was
added to three equivalents of ethyl(iodomethyl)zinc before the
addition of methyl benzoylacetate (9), a second regioisomer 11 was
formed in addition to the desired product 12 (Scheme 2). The for-
mation of the isomer 1 may be due to formation of small quantities
of tricarbonyl 10 before homologation of 9 has had a chance to
occur. Compound 17 contains two ketones that provide competing
sites for methylene insertion in the homologation reaction.
Upon optimization of the tandem homologation-acylation
(
g
6
b
acidic proton capable of quenching unreacted organometallic
compound 5, thereby providing the simple homologated product
(
6). Once compound 7 is deprotonated, the zinc enolate can react
with another equivalent of carbenoid to produce compound 8. The
yield of the desired product (7) was greatly improved by treatment
of methyl pivaloylacetate with three equiv of diethylzinc, followed
by one equiv of diiodomethane and finally 1.5 equiv of acetic an-
hydride (Table 1, entry 2). The first equiv of diethylzinc served to
deprotonate methyl pivaloylacetate (4), while a second equivalent
reacted with diiodomethane to form the carbenoid required for
conditions, a range of
b-keto carbonyl substrates and acylating
agents were examined with respect to the efficiency of the reaction
(Table 2). Benzoic anhydride and isobutyric anhydride (Table 2,
entries 2 and 3) typically provided higher yields than acetic anhy-
dride, suggesting that bulkier acylating agents were more efficient.
homologation of the
b-keto ester. Since only one equivalent of
carbenoid was generated, the further homologation of compound 7
to provide 8 was avoided. The third equivalent of diethylzinc was
necessary to remove the acidic proton on acylated compound 7,
The range of b-keto esters demonstrates that bulky or aromatic
preventing the organometallic intermediate
5
from being
substituents on the ketone or ester do not compromise the effi-
ciency of the tandem reaction sequence. When allyl acetoacetate or
t-butyl acetoacetate (Table 2, entries 4e7) were used as starting
materials, lower yields of products were obtained. These reduced
yields may be due to Lewis acid-catalyzed decomposition of the
esters or due to the susceptibility of the olefin to cyclopropanation
Table 1
Optimization of tandem chain extension-acylation reaction using methyl piv-
aloylacetate.
when in the presence of zinc-carbenoid. Use of a
amide (15) and -keto imide (16) (Table 2, entries 10 and 11) in the
tandem reaction also proved to be suitable for the production of
acylated -keto compounds.
b-keto tertiary
b
g
In addition to the use of anhydrides, alternate acylating agents
were investigated. Use of phenyl formate as the electrophile
resulted in a complex reaction mixture with no evidence of the
desired product. Treatment of methyl benzoylacetate with the zinc
carbenoid followed by addition of acetyl chloride resulted in for-
mation of the unsubstituted
g-keto ester 26 [21] through protic
quenching of the organometallic intermediate (Scheme 3). The
source of the proton may have been residual HCl generated from
acetyl chloride or from the acetyl chloride's acidic a-proton. Efforts
to purify acetyl chloride were not successful in prohibiting protic
quenching. Additional reactions with acid chlorides provided
similar results.
Benzotriazole-activated acetic acid (27) [22] could be used as an
acylating agent with moderate success (Scheme 4), a result that
stands in contrast to an earlier report [16]. In addition, Boc-
protected lactam 28 [23] was reacted with compound 4 using the
optimized homologation-acylation conditions (Scheme 4). This
successfully provided compound 36 as a mixture of constitutional
and configurational isomers.
O (equiv) 6(%)a 7(%)a
2
8(%)a
Entry Et
2
Zn (equiv) CH
2
I
2
(equiv) Ac
1
2
3
3
3
4
3
1
4
1
30
17
28
24
46
0
61
83 (63)b
1.5
1
c
11
a
Relative abundance using relative integrations from 1H NMR analysis of the
crude reaction mixture.
b
Isolated yield of purified material.
c
Diethylzinc and methyl pivaloylacetate were stirred for 10 min prior to adding
diiodomethane.
Utility of the tandem homologation acylation reaction in
2

C.S. Henderson, J.R. Mazzone, A.M. Moore et al.
Tetrahedron xxx (xxxx) xxx
Scheme 2. Formation of regioisomers in the homologation-acylation reaction.
Table 2
Tandem chain-extension acylation of (b)-keto carbonyls.
Entry
SM
R1
R2
R3
Product
Yield (%)
1
2
3
4
5
6
7
8
9
4
4
4
t-Bu
t-Bu
t-Bu
Me
Me
Me
Me
Ph
-OMe
-OMe
-OMe
-Ot-Bu
-Ot-Bu
Me
i-Pr
Ph
Me
Ph
Me
Ph
Me
Ph
7
63
80
95
50
46
44
55
50
65
81
53
17
18
19
20
21
22
12
23
24
25
13
13
14
14
9
9
15
16
-OCH
-OCH
2
CH]CH
CH]CH
2
2
2
-OMe
-OMe
-NMe
Ph
Me
1
1
0
1
2
Ph
Ph
application to the synthesis of the papyracillic acid [20] family of
natural products required the use of a cyclic anhydride to trap the
organometallic intermediate (2). A broader investigation of tandem
anhydride gave rise to a mixture of products (Scheme 5). Close
examination of the crude reaction mixture by NMR spectroscopy
revealed that maleic anhydride did indeed trap the homologated
intermediate through an acylation reaction. A similar result, which
reactions that utilized cyclic anhydrides with various starting
dicarbonyls was undertaken. Treatment of methyl pivaloylacetate
4) with ethyl(iodomethyl)zinc followed by addition of maleic
b-
includes isomerization of the alkene, was observed when
b-keto
(
imide (33) [14] was subjected to the same homologation reaction
Scheme 3. Attempted acylation with acetyl chloride.
3

C.S. Henderson, J.R. Mazzone, A.M. Moore et al.
Tetrahedron xxx (xxxx) xxx
Scheme 4. Acylation with alternative electrophiles.
Scheme 5. Tandem chain-extension acylation with cyclic anhydrides.
conditions. Succinic anhydride (35) was also explored as an acyl-
ating agent. Exposure of methyl pivaloylacetate (4) to carbenoid
followed by addition of succinic anhydride produced a mixture of at
least three isomeric compounds. Analysis of the NMR spectra
revealed the presence of ketal resonances, which affirmed that the
spiroketal core could be formed directly through a tandem
homologation-acylation reaction. These results were consistent
with the observations made when using methoxymaleic anhydride
in our synthetic route to the papyracillic acid family of natural
products [19].
As suggested by the inadvertent formation of 15 during opti-
mization studies, zinc carbenoid-mediated homologation of the
4

C.S. Henderson, J.R. Mazzone, A.M. Moore et al.
Tetrahedron xxx (xxxx) xxx
Scheme 6. Sequential homologation reactions.
acylated product should be possible. The potential for additional
homologation was confirmed (Scheme 6) by the successful for-
mation of 37 in 69% by treatment of compound 18 with three equiv
of ethyl(iodomethyl)zinc.A one-pot tandem reaction featuring
homologation-acylation-homologation was developed by treating
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
b
-keto ester starting materials with a greater excess of carbenoid
The authors would like to acknowledge support provided by the
University of New Hampshire and that of the National Institutes of
Health (R15 GM060967-03).
and the use of longer reaction times. For example, treatment of
compound 4 with excess carbenoid for 3.5 h in the presence of an
anhydride provided compounds 8 and 38 in 63% and 57%, respec-
tively. One-pot double homologation of methyl acetoacetate (39) to
form 40 was also successfully accomplished, albeit in a modest 23%.
Efforts to perform double homologation reactions that involved
acylation with benzoic anhydride were unsuccessful. For example,
exposure of 9 to carbenoid and benzoic anhydride provided 23, the
result of single homologation, regardless of the number of equiv-
alents of carbenoid and reaction time. This result is consistent with
the inability to perform further homologation of purified 23.
In summary, a tandem chain extension-acylation reaction has
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132223.
References
[1] a) H. Veisi, R. Azadbakht, M. Ezadifar, S. Hemmati, J. Het. Chem. 50 (2013)
E241eE246;
b) A. Ramirez-Rodriguez, J.M. Mendez, C.C. Jimenez, F. Leon, A.A. Vazquez,
Synthesis 44 (2012) 3321e3326.
been developed to produce a-acylated g-keto carbonyls. Cyclic and
acyclic anhydrides, benzotriazole-activated carboxylic acids, and
cyclic imides were shown to be effective acylating agents. The
tandem homologation acylation reaction proceeds in modest to
good yields when starting from a diverse array of b-keto carbonyl
compounds. Rapid assembly of differentially functionalized 1,4-
diketones products is available from this method.
[2] a) G. Yin, Z. Wang, A. Chen, M. Gao, A. Wu, Y. Pan, J. Org. Chem. 73 (2008)
3
377e3383;
b) I. Truel, A. Mohamed-Hachi, E. About-Jaudet, N. Collignon, Synth. Commun.
7 (1997) 1165e1171.
[3] E. Campaigne, W.O. Foye, J. Org. Chem. 17 (1952) 1405.
2
[
[
[
[
4] L.N. Aldrich, C.B. Berry, B.S. Bates, L.C. Konkol, M. So, C.W. Lindsley, Eur. J. Org
Chem. (2013) 4215e4218.
5] S.K. Mahato, J. Vinayagam, S. Dey, A.K. Timiri, S. Chatterjee, P. Jaisankar, Aust. J.
Chem. 66 (2013) 241e251.
6] A.V. Butin, T.A. Nevolina, V.A. Shcherbinin, M.G. Uchuskin, O.V. Serdyuk,
I.V. Trushkov, Synthesis 17 (2010) 2969e2978.
7] J. Furukawa, N. Kawabata, J. Nishimura, Tetrahedron 24 (1968) 53e58.
Declaration of competing interest
The authors declare that they have no known competing
[8] J.B. Brogan, C.K. Zercher, J. Org. Chem. 62 (1997) 6444e6446.
5

C.S. Henderson, J.R. Mazzone, A.M. Moore et al.
9] R. Hilgenkamp, C.K. Zercher, Tetrahedron 57 (2001) 8793e8800.
Tetrahedron xxx (xxxx) xxx
[
J. Comb. Chem. 8 (2006) 491e499.
[
[
10] C.A. Verbicky, C.K. Zercher, J. Org. Chem. 65 (2000) 5615e5622.
11] W. Lin, R.J. McGinness, E.C. Wilson, C.K. Zercher, Synthesis 15 (2007)
[17] G. Minetto, L.F. Raveglia, A. Sega, M. Taddei, Eur. J. Org Chem. (2005)
5277e5288.
2
402e2408.
[18] C.W. Bird, G.W.H. Cheeseman, Comprehensive Heterocyclic Chemistry, vol. 4,
Pergamon, Oxford, 1984.
[
[
[
12] R. Hilgenkamp, C.K. Zercher, Org. Lett. 3 (2001) 3037e3040.
13] M.D. Ronsheim, C.K. Zercher, J. Org. Chem. 68 (2003) 4535e4538.
14] A.M. Jacobine, A. Puchlopek, C.K. Zercher, J.B. Briggs, J.P. Jasinsky, Tetrahedron
[19] J.R. Mazzone, C.K. Zercher, J. Org. Chem. 77 (2012) 9171e9178.
[20] J. Dai, K. Krohn, B. Els €a sser, U. Fl o€ rke, S. Draeger, B. Schulz, G. Pescitelli,
P. Salvadori, S. Antus, T. Kurt aꢀ n, Eur. J. Org Chem. (2007) 4845e4854.
[21] W. Ren, M. Yamane, J. Org. Chem. 75 (2010) 3017e3020.
[22] A.R. Katritzky, A. Pastor, J. Org. Chem. 65 (2000) 3679e3682.
[23] F. Crestey, G. Hooyberghs, J.L. Kristensen, Tetrahedron 68 (2012) 1417e1421.
6
8 (2012) 7799e7805.
15] S. Lai, C.K. Zercher, J.P. Jasinsky, S.N. Reid, R.J. Staples, Org. Lett. 3 (2001)
169e4171.
16] I. Bianchi, R. Forlani, G. Minetto, I. Peretto, N. Regalia, M. Taddei, L.F. Raveglia,
[
[
4
6