Intercepted decarboxylative allylations of nitroalkanoates

Article abstract of DOI:10.1016/j.tetlet.2012.05.138

Using palladium-catalyzed decarboxylation, several cascade reactions of allyl and prenyl nitroalkanoates that lead to nitro-containing chemical building blocks are described. A nitronate Michael addition/Tsuji-Trost allylation cascade was developed, leading to functionally dense chemical building blocks. Likewise, a Tsuji-Trost/decarboxylative protonation sequence was developed for the synthesis of orthogonally functionalized 2° nitroalkanes. The latter method provides rapid access to the indolizidine core.

Full text of DOI:10.1016/j.tetlet.2012.05.138

Tetrahedron Letters 53 (2012) 4494–4497
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intercepted decarboxylative allylations of nitroalkanoates
⇑
Meghan Schmitt, Alexander J. Grenning, Jon A. Tunge
The University of Kansas, Department of Chemistry 2010 Malott Hall, 1251 Wescoe Hall Dr., Lawrence, KS 66045, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Using palladium-catalyzed decarboxylation, several cascade reactions of allyl and prenyl nitroalkanoates
that lead to nitro-containing chemical building blocks are described. A nitronate Michael addition/Tsuji–
Trost allylation cascade was developed, leading to functionally dense chemical building blocks. Likewise,
a Tsuji–Trost/decarboxylative protonation sequence was developed for the synthesis of orthogonally
functionalized 2° nitroalkanes. The latter method provides rapid access to the indolizidine core.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 3 May 2012
Revised 25 May 2012
Accepted 29 May 2012
Available online 7 June 2012
Keywords:
Decarboxylative coupling
Pd-catalysis
Multi-component reactions
Tsuji–Trost allylation
Indolizidine alkaloids
Introduction
cascade strategy to access functional allylated 2° nitroalkanes
(Scheme 3).
Palladium-catalyzed decarboxylative allylation (DcA) is a con-
venient method to generate functionalized chemical building
blocks with only CO2 as a byproduct.1,2 Using this chemical reactiv-
ity, various methods have been developed for the synthesis of
nitrogen-containing chemical building blocks.3 This is of signifi-
cance since nitrogen-containing materials often exhibit interesting
biological activities. In this regard, we reported the rapid decarb-
oxylative allylation of nitroalkanes (Scheme 1).4 Nitroalkanes read-
ily allow the incorporation of nitrogen into alkaloids and other
biologically active nitrogenous compounds because they have the
advantageous chemical properties of a relatively low pKa (ꢀ10 in
H2O)5 and facile reducibility to amines. As shown in Scheme 1, nit-
O
+
1) facile reactant synthesis
2) DcA
H2N
O2N
O
3) reduction
H2C=O
CO2Allyl
DcA
O2N
O2N
Pd
O2N
R R
roacetic esters are readily functionalized by
Decarboxylative allylation then provides tertiary nitroalkanes that
a
-alkylation.6,7
are readily reduced to amines.
Scheme 1. DcA of allyl nitroalkanoates.
One advantage of the DcA of nitroalkanes is that it allows the
generation of reactive nucleophiles and electrophiles in situ. We
and others have previously demonstrated that these nucleophilic
and electrophilic coupling partners can be funneled down alternate
reaction pathways such as Michael-addition/Tsuji–Trost allylation
cascades (interceptive DcA)1,8 or capture by protonation.9 Herein
we report that allyl nitroalkanoates can participate in similar cas-
cade reactions. We present a Michael-addition/Tsuji–Trost cascade
leading to functionally dense nitro group-containing compounds
(Scheme 2) as well as a Tsuji–Trost/decarboxylative protonation
O
Pd
Pd(PPh3)4
CO2
O2N
R R
O2N
O
R'
R'
R R
Ph
Z
Ph
O2N
Z
R'
Z = electron with drawing group
R R Z
Z
⇑
Corresponding author.
E-mail address: tunge@ku.edu (J.A. Tunge).
Scheme 2. Cascade Michael addition/Tsuji–Trost allylation initiated by decarbox-
ylation of allyl nitroalkanoates.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.138

M. Schmitt et al. / Tetrahedron Letters 53 (2012) 4494–4497
4495
Table 2
O
Pd(0)
O
Interceptive decarboxylative allylation of allyl nitroalkanoates with Meldrum’s acid
derived Michael acceptors
MeO2CO
Pd(PPh3)4
O2N
R'
O2N
O
O
R
O
O
Ph
O
O
O2N
O2N
5 mol%
O
O
R
O
Pd(PPh3)4
- CO2 and
isoprene
O2N
H
N
R
Ph
R
O
O
R
O
1b,f
3a-b
O
Scheme 3. Cascade Tsuji–Trost/decarboxylative protonation of allyl nitroalkanoates.
Table 1
Interceptive decarboxylative allylation of allyl nitroalkanoates with benzylidenemal-
ononitrile
Ph
Ph
O
CN
CN
Pd(0)a O2N
CN
O2N
O
R
R
R
R
R
CN
1
2a-g
Ph
Ph
Ph
O2N
O2N
CN
CN
CN
CN
CN
CN
O2N
O2N
MeOC
O2N
COMe
68%
2b
2a 97%
88%
2c
Ph
Ph
Ph
O2N
CN
CN
CN
CN
CN
CN
a
The relative configuration of the major diastereomer is not known.
R
tion, the diastereomers of 2g could be chromatographically
separated. The successful synthesis of prenylated product 2g was
particularly gratifying given that attempted decarboxylative pre-
nylation of 1a led primarily to the protonation product (Eq. 1).
b,d
2d 89%b, 86%b,c
2e
2f
2g 92%b,d
R = Ph, 74%
b,d
R = Pr, 98%
a Reaction conditions: 1:1 1: benzylidenemalononitrile, 5 mol % Pd(PPh3)4, DCM, rt,
12 h.
1:1 d.r.
While palladium-p prenyl complexes often undergo b-elimination
b
c
instead of the desired C–C linkage, prenylation methodologies have
Toluene in lieu of DCM, rt, 12 h.
been developed for some nucleophiles.10
d
>20:1 linear: branched.
Having demonstrated that the Michael addition/Tsuji–Trost
cascade process was successful with benzylidenemalononitrile,
we wished to extend this methodology to Michael acceptors
derived from Meldrum’s acid (Table 2). Surprisingly, the reaction
failed to produce any of the desired product under the same condi-
tions developed for benzylidenemalononitrile (Table 2, entry 1).
Furthermore, heating the reactants at various temperatures in
chlorinated solvents failed to give a desirable result (Table 2, en-
tries 2–3). Fortunately, good yields could be achieved in THF (entry
4) or toluene (entry 5). Interestingly, a modest diastereoselectivity
was observed, though different solvents did not affect this ratio.
Aside from simple unsubstituted allyl esters, the alkyl-substituted
hexenyl nitroalkanoate provided a modest yield of the Michael
addition/Tsuji–Trost coupling product (entry 6). Simple cyclopen-
tyl allyl nitroalkanoate could also undergo a clean reaction in
75% isolated yield (Eq. 2, 3c).
Michael addition/Tsuji–Trost allylation cascades
To begin, we treated allyl nitroalkanoates under similar condi-
tions to those developed for the successful DcA reaction of allyl
nitroalkanoate (5 mol % Pd(PPh3)4, DCM),4 however an equivalent
of benzylidenemalononitrile was included in the reaction mixture.
Gratifyingly, the intermediate allyl electrophile and nitronate
nucleophiles were intercepted with the benzylidene malononitrile
to form highly functionalized nitroalkanes (Table 1). The inter-
cepted DcA reaction was not nearly as rapid as the standard DcA
reaction, requiring 12 h for completion. The uninterrupted decarb-
oxylative allylation reaction of allyl nitroalkanoates required < 5
minutes to achieve completion under the same conditions.4 The
slower rate of interceptive DcA is easily explained by the coordina-
tion of benzylidene malononitrile to Pd(0), rendering the catalyst
less electron-rich and less prone to undergo oxidative addition
with the allylic carboxylate. Nonetheless, various allyl nitroalkano-
O
O2N
5 mol %
Pd(PPh3)4
O2N
H
O
ates were excellent coupling partners (2a–d). a,a-Dialkyl nitroalk-
ð1Þ
ð2Þ
anes (2a,b), including Michael (2c)7 and Knoevenagel/Diels–Alder
(2d) adducts6 were compatible coupling partners. It was unfortu-
nate, though not surprising, that Diels–Alder adduct 2d was
formed with no diastereoselection; changing the solvent from
DCM to toluene did not improve the diastereoselectivity, but the
cascade reaction progressed comparably well. Aside from allyl
nitroalkanoate (2a–d), cinnamyl, hexenyl, and prenyl nitroalkano-
ates were excellent coupling partners (2e–g), giving exclusively the
linear product. Although 2e–g were formed with no diastereoselec-
DCM, 5 min.
75%
MeOC
MeOC
O2N
1a
O
O
5 mol%
Pd(PPh3)4
O
O
Ph
O
O
O2N
O
O
75%
O
Ph
O
3c

4496
M. Schmitt et al. / Tetrahedron Letters 53 (2012) 4494–4497
We also attempted to utilize nitrostyrenes as coupling partners
O
O2N
O
for interceptive DcA (Eq. 3). Unfortunately, there appears to be no
driving force for the Michael addition to form 4, and DcA to
produce 5 was the only reaction pathway observed (Eq. 3).4 In
the successful examples of interceptive DcA, the anion generated
upon Michael addition is always more stable than that of the initial
nucleophile. Thus, there is a thermodynamic driving force for reac-
tion progression. Comparison of the relevant pKa values (in DMSO)
further illuminates the driving force for nitronate (pKa ꢀ17)
addition to malononitriles (pKa ꢀ12) and Meldrum’s acid adducts
(pKa ꢀ7.5).5 Moreover, our results trend with Mayr’s observation
that Michael acceptors derived from malononitrile and Melrum’s
a,b,c
d
Pr
N
Pr
N
O
Pr
7b
8
9
(a) 20 Equiv.Zn Dust, 10 Equiv. HCl, iPrOH (b) DIBALH, DCM -78oC-rt
(c) 1.1 equiv. acryloyl chloride, 1.2 equiv. pyridine, DCM 0 oC - rt
(3-steps 65% yield) (d)5 mol% Grubbs' II, tol, 60 oC 2 h, 88% yield.
Scheme 4. Synthesis of the indolizidine core.
acid are more electrophilic than a Pd-p
-allyl complex,11 thus addi-
30 °C. The palladium catalyst first effects the Tsuji–Trost allylation
of the nitroalkanoate. Upon warming, this reaction is followed by
decarboxylative protonation to yield secondary nitroalkanes 7a
and 7b in good yields. Moreover, synthetically useful quantities
(>1 g) of 7b were prepared for further chemical manipulation.
To demonstrate the utility of this process, compound 7b was
then converted to the indolizidine core in 4 steps (Scheme 4). Upon
reduction of the nitro group,6 spontaneous condensation to the
imine occurred.11 This imine was immediately reduced to cis-1,
5-pyrrolidine as a single diastereomer.15 As purification of this sec-
ondary amine was deemed too challenging, it was not purified un-
til after acylation with acryloyl chloride. This 3-step process
progressed in 65% overall yield. Interestingly, this amide exists as
a 1:1.2 mixture of rotamers about the amide-bond. Fortunately,
heating with Grubbs’ second generation catalyst (5 mol %), the dia-
stereomers underwent convergent metathesis leading to a single
ring-closed product 9 in 88% yield.
tion of nitronates to benzylidene malononitriles is expected to be
kinetically faster than allylation.
O2N
O
5 mol%
O2N
5
Pd(PPh3)4
(-CO2)
(99%)
Ph
NO2
O
ð3Þ
Ph
+
O2N
NO2
4
(0%)
Michael addition/Tsuji–Trost allylation cascades
In conclusion, we have shown that nitronates and Pd-p-allyl
complexes derived from allyl nitroalkanoates can be diverted from
decarboxylative allylation (DcA) through reaction pathways
including Michael addition/Tsuji–Trost cascades and Tsuji–Trost/
decarboxylative protonation reactions.
In addition to the development of the Michael addition/Tsuji–
Trost cascades initiated by decarboxylation, we were intrigued by
the clean conversion of the prenyl nitroalkanoate into the proton-
ated 2° nitroalkane product (Eq. 1). Historically, allylated 2° nitro-
alkanes can be challenging to access due to competing over
alkylation. Thus, the nitroalkane nucleophile is commonly used
in excess to selectively give the 2° nitroalkane.12 Clearly, this is
an unattractive solution if one wishes to utilize precious nitroal-
kane reactants. Since nitroalkanoates are excellent Tsuji–Trost sub-
strates,13 we proposed that a single pot Tsuji–Trost allylation/
decarboxylative protonation strategy could quickly lead to syn-
thetically useful 2° nitroalkanes (Scheme 3). Moreover, with appro-
priate substitution, functional groups can be paired to quickly
access cis-1,5-dialkyl pyrrolidines and the indolizidine core.14,15
Acknowledgment
We acknowledge the National Institute of General Medical Sci-
ences (NIGMS 1RO1GM079644) for funding.
Supplementary data
Supplementary data (detailed experimental analysis and spec-
tral analysis including 1H, 13C, and HRMS or GC–MS) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2012.05.138.
O
O2N
O2N
OCO2Me
O
References and notes
50 mol% DBU,
1. Weaver, J. D.; Recio, A., III; Grenning, A. J.; Tunge, J. A. Chem. Rev. 1846, 2011, 111.
2. For select examples of decarboxylative allylation of carbon-nucleophiles see:
(a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21, 3199; (b) Tsuda,
T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am. Chem. Soc. 1980, 102, 6381;
(c) Recio, A., III; Tunge, J. A. Org. Lett. 2009, 11, 5630; (d) Weaver, J. D.; Tunge, J.
A. Org. Lett. 2008, 10, 4657; (e) Weaver, J. D.; Ka, B. J.; Morris, D. K.; Thompson,
W.; Tunge, J. A. J. Am. Chem. Soc. 2010, 132, 12179; (f) Burger, E. C.; Tunge, J. A. J.
Am. Chem. Soc. 2006, 128, 10002; (g) Trost, B. M.; Bream, R. N.; Xu, J. Angew.
Chem., Int. Ed. 2006, 45, 3109; (h) Hong, A. Y.; Krout, M. R.; Jensen, T.; Bennett,
N. B.; Harned, A. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2011, 50, 2756; (i) Mohr,
J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2005, 44,
6924; (j) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343.
3. (a) Yeagley, A. A.; Chruma, J. J. Org. Lett. 2007, 9, 2979; (b) Fields, W. H.; Khan, A.
K.; Sabat, M.; Chruma, J. J. Org. Lett. 2008, 10, 5131; (c) Waetzig, S. R.; Tunge, J.
A. J. Am. Chem. Soc. 2007, 129, 14860; (d) Waetzig, S. R.; Tunge, J. A. J. Am. Chem.
Soc. 2007, 129, 4138.
5 mol% Pd(PPh3)4,
O
R
DCM -30 oC - rt
O
R
7a R = Me, 86%
7b
6a
R = Me
R = Pr, 90%
ð4Þ
6b R = Pr
O
O2N
Pd
cat
Pd
cat
O
O
R
We began by synthesizing substrates 6 from prenyl nitroalk-
anoate using Yb(OTf)3-catalyzed Michael additions (Eq. 4).7b Once
the nitroalkanoates were alkylated with the vinyl ketone, sub-
strates 6 were allowed to react with allyl carbonate in the presence
of catalytic amounts of DBU (50 mol %) and Pd(PPh3)4 (5 mol %) at -
4. Grenning, A. J.; Tunge, J. A. Org. Lett. 2010, 12, 740.
5. Prof. Hans Reich has compiled
a useful list of pKa’s in DMSO: http://
www.chem.wisc.edu/areas/reich/pkatable/index.htm.
6. Nitroalkanoates undergo facile Knoevenagel/Diels–Alder reactions: (a) Wade,
P. A.; Murray, J. K.; Shah-Patel, S.; Carroll, P. J. Tetrahedron Lett. 2002, 43, 2585;

M. Schmitt et al. / Tetrahedron Letters 53 (2012) 4494–4497
4497
(b) Butt, N. A.; Moody, C. J. Org. Lett. 2011, 13, 2224; (c) Jayakanthan, K.; Vankar,
Y. D. Org. Lett. 2005, 7, 5441.
7. For examples of Michael addition to nitroalkanoates: (a) Keller, E.; Feringa, B. L.
Synlett 1997, 842; (b) Aplander, K.; Ding, R.; Krasavin, M.; Lindstrom, U. M.;
Wennerberg, J. Eur. J. Org. Chem. 2009, 810.
8. See Ref. 1 for a review of IDcA. For leading references on IDcA see: (a) Nokami,
J.; Watanabe, H.; Mandai, T.; Kawada, M.; Tsuji, J. Tetrahedron Lett. 1989, 30,
4829; (b) Wang, C.; Tunge, J. A. J. Am. Chem. Soc. 2008, 130, 8118; (c) Patil, N. T.;
Yamamoto, Y. Synlett 2007, 1994; (d) Shim, J.-G.; Nakamura, H.; Yamamoto, Y. J.
Org. Chem. 1998, 63, 8470; (e) Shintani, R.; Park, S.; Hayashi, T. J. Am. Chem. Soc.
2007, 129, 14866; (f) Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem.
2010, 2, 192.
9. (a) Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006,
128, 11348; (b) Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett.
2008, 10, 1039.
11. (a) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66; (b) Kaumanns,
O.; Mayr, H. J. Org. Chem. 2008, 73, 2738–2745; (c) Zenz, I.; Mayr, H. J. Org.
Chem. 2011, 76, 9370.
12. (a) Aleksandrowicz, P.; Piotrowska, H.; Sas, W. Tetrahedron 1982, 38, 1321; (b)
Wade, P. A.; Morrow, S. D.; Hardinger, S. A. J. Org. Chem. 1982, 47, 365; (c)
Deardorff, D. R.; Savin, K. A.; Justman, C. J.; Karanjawala, Z. E.; Sheppeck, J. E., II;
Harger, D. C.; Aydin, N. J. Org. Chem. 1996, 61, 3616; (d) Trost, B. M.; Surivet, J.-
P. J. Am. Chem. Soc. 2000, 122, 6291; (e) Trost, B. M.; Surivet, J.-P. Angew. Chem.,
Int. Ed. 2000, 39, 3122; (f) Maki, K.; Kanai, M.; Shibasaki, M. Tetrahedron 2007,
63, 4250.
13. (a) Ono, N.; Hamamoto, I.; Kaji, A. J. Org. Chem. 1986, 51, 2832; (b) Genet, J. P.;
Ferroud, D. Tetrahedron Lett. 1984, 25, 3579; (c) Fu, Y.; Etienne, M. A.; Hammer,
R. P. J. Org. Chem. 2003, 68, 9854; (d) Tsuji, J.; Yamada, T.; Minami, I.; Yuhara,
M.; Nisar, M.; Shimizu, I. J. Org. Chem. 1987, 52, 2988.
14. Comer, E.; Rohan, E.; Deng, L.; Porco, J. A. Org. Lett. 2007, 9, 2123.
15. Bacos, D.; Célérier, J. P.; Marx, E.; Saliou, C.; Lhommet, G. Tetrahedron Lett. 1989,
30, 1081.
10. (a) Prenylation can often be challenging due to competing elimination but
works best with highly stabilized anions: Ref. 1 and references therein.; (b)
Trost, B. M.; Malhotra, S.; Chan, W. H. J. Am. Chem. Soc. 2011, 133, 7328. and
references therein.