Conjugate addition of lithiated methyl pyridines to enones

Article abstract of DOI:10.1021/jo100890s

Preparatively useful conjugate addition of lithiated methyl pyridines to cyclic and acyclic enones is reported. Addition of 2-picoline to 3-penten-2-one led to a concise synthesis of the alkaloids (±)-senepodine G and (±)-cermizine C.

Full text of DOI:10.1021/jo100890s

pubs.acs.org/joc
However, such a conjugate addition had been consistently
Conjugate Addition of Lithiated Methyl
Pyridines to Enones
reported not to be successful.4a,b Here, we report the success-
ful conjugate addition of lithiated methyl pyridines to cyclic
and acyclic enones and the use of this method in a simple pre-
paration of the alkaloids (()-senepodine G and (()-cermizine
C. We note that as this work was ready for publication, a
parallel account of the successful conjugate addition of lithi-
ated 2-picoline to cyclohexenone appeared4c that enabled a
concise synthesis of (()-lycopladine A.
Douglass F. Taber,* Pengfei Guo, and Michael T. Pirnot
Department of Chemistry and Biochemistry, University of
Delaware, Newark, Delaware 19716
taberdf@udel.edu
SCHEME 1
Received May 4, 2010
Preparatively useful conjugate addition of lithiated methyl
pyridines to cyclic and acyclic enones is reported. Addition
of 2-picoline to 3-penten-2-one led to a concise synthesis
of the alkaloids (()-senepodine G and (()-cermizine C.
Development of the Method. Recent efforts by others toward
the 1,4-conjugate addition of metalated 2-picoline had shown
that although the conjugate addition to R,β-unsaturated esters
was successful, conjugate addition with enones was poor, lead-
ing mainly to the 1,2-addition product.4a,b We have examined
in detail (Table 1) the conjugate addition of metalated 2-pico-
line to cyclohexenone. We reasoned that it might be a problem
to make cuprate reagent from lithium reagent at 0 °C, as had
been described,4a,b as it could decompose at that temperature.5
Thus, we modified the procedure and prepared the cuprate at
-30 °C. We were pleased to find that the conjugate addition
worked for cyclohexenone, giving a 3:1 ratio of the separable
1,4- and 1,2-products in 79% combined yield (entry 1). More
soluble copper salts improved the ratio (entries 2 and 4). Ratios
were still better when the addition was carried out at lower
temperature (entries 5 and 6).
Pyridine and piperidine rings are not only ubiquitous
structures in complex and physiologically active natural pro-
ducts but also versatile building blocks in synthetic organic
chemistry.1 In connection with an ongoing project on the
synthesis of alkaloid (()-cermizine C, we envisioned con-
jugate addition of metalated 2-picoline to an enone (Scheme 1).
The existing alternative, as employed2 in a recent asymmetric
total synthesis of (þ)-lycopladine A, has been the assembly
of substituted pyridines from 1-azatrienes by a cascade
sequence involving double-bond isomerization, 6π electro-
cyclization, and elimination of the amine.3 Conjugate addi-
tion of the metalated 2-picoline would be much more direct.
TABLE 1. Optimization of the Conjugate Addition
(1) (a) Saporito, R. A.; Donnelly, M. A.; Jain, P.; Garraffo, H. M.;
Spande, T. F.; Daly, J. W. Toxicon 2007, 50, 757–778. (b) Morita, H.;
Hirasawa, Y.; Shinzato, T.; Kobayashi, J. Tetrahedron 2004, 60, 7015–7023.
(c) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–446. (d) O’Hagan, D. Nat.
Prod. Rep. 1997, 14, 637–651. (e) Serrano, M. A. R.; Pivatto, M.; Francisco,
W.; Danuello, A.; Regasini, L. O.; Lopes, E. M. C.; Lopes, M. N.; Young,
M. C. M.; Bolzani, V. S. J. Nat. Prod. 2010, 73, 482–484. (f) Kesting, J. R.;
Tolderlund, I.; Pedersen, A. F.; Witt, M.; Jaroszewski, J. W.; Staerk, D.
J. Nat. Prod. 2009, 72, 312–315. (g) Viegas, C.; Silva, D. H. S.; Pivatto, M.;
Rezende, A.; Castro-Gamboa, I.; Bolzani, V. S.; Nair, M. G. J. Nat. Prod.
2007, 70, 2026–2028. (h) Nunez, M. J.; Guadano, A.; Jimenez, I. A.; Ravelo,
A. G.; Gonzalez-Coloma, A.; Bazzocchi, I. L. J. Nat. Prod. 2004, 67, 14–18.
(i) Larson, K. K.; Sarpong, R. J. Am. Chem. Soc. 2009, 131, 13244–13245.
(j) Gribkov, D. V.; Pastine, S. J.; Schnurch, M.; Sames, D. J. Am. Chem. Soc.
2007, 129, 11750–11755. (k) Zhou, J.; List, B. J. Am. Chem. Soc. 2007, 129,
7498–7499.
combined
CuX (equiv) temp (°C) 1,4:1,2 yielda (%)
entry
CuX
CuCN
CuCN2LiCI
Cul
CuBrSMe2
CuCN2LiCI
CuBrSMe
1
2
3
4
5
6
2
2
2
2
2
2
-20
-20
-20
-20
-78
-78
3:1
79
90
88
89
87
94
4.5:1
2.8:1
4.2:1
6.3:1
7:1
aCombined yields are for pure isolated products.
(2) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.;
LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991–5994.
(3) (a) Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S. J. Org.
Chem. 2001, 66, 3099–3110. (b) Verboom, W.; Vaneijk, P. J. S. S.; Conti,
P. G. M.; Reinhoudt, D. N. Tetrahedron 1989, 45, 3131–3138.
We briefly examined the scope of this optimized (Table 1,
entry 6) conjugate addition (Table 2). The reaction with
(4) (a) Sanchez-Sancho, P.; Herradon, B. Heterocycles 2003, 60, 1843–
1854. (b) Borne, R. F.; Aboul-Enein, H. Y. J. Heterocycl. Chem. 1972, 933–
934. (c) DeLorbe, J. E.; Lotz, M. D.; Martin, S. F. Org. Lett. 2010, 12,
1576.
(5) For the thermal instability of organocuprates, see: (a) House, H. O.;
DuBose, J. C. J. Org. Chem. 1975, 40, 788. (b) Rahman, M. T.; Hoque, A. K.
M. M.; Siddique, I.; Chowdhury, D. A. N.; Nahar, S. K.; Saha, S. L.
J. Organomet. Chem. 1980, 188, 293.
DOI: 10.1021/jo100890s
r
Published on Web 07/20/2010
J. Org. Chem. 2010, 75, 5737–5739 5737
2010 American Chemical Society

Taber et al.
JOCNote
TABLE 2. Conjugate Addition of Lithiated Pyridines to Enones
SCHEME 2
epi-senepodine G. Direct reduction of each with NaBH4
delivered7 the alkaloids (()-cermizine C (13) and (()-epi-
cermizine C (14), each as a single diastereomer, allowing
assignment of the structures of 9 and 10.
aYields are for pure isolated conjugate addition products. Additions
were carried out by the method of Table 1, entry 6. The corresponding
1,2-adducts were observed but were not characterized. bReference 4c.
Conclusion
We have established a procedure for the conjugate addi-
tion of lithiated methyl pyridines to enones that we think will
be generally useful. This protocol allows an efficient assem-
bly of synthetically valuable pyridines and piperidines. The
utility of this reaction was demonstrated by the concise syn-
thesis of (()-senepodine G (four steps) and (()-cermizine C
(five steps). We expect that this conjugate addition protocol
will have many applications both in natural product synthe-
sis and in medicinal chemistry.
different ring-sized cyclic enones proceeded efficiently. For
the acyclic enone, conjugate addition delivered the 1,4-product
in moderate yield. It is also noteworthy that 2,6-lutidine
participated smoothly (entry 3). Conjugate addition with
metalated 2,4,6-collidine led to the ortho-substituted deri-
vative 4 and the para-substituted derivative 5 in a statistical
2:1 ratio (entry 4). With the results reported here, the conju-
gate addition of lithiated methyl pyridines to enones appears
to be a generally applicable synthetic method.
Experimental Section
Synthesis of (()-Senepodine G and (()-Cermizine C. The
utility of this method for the formation of pyridine and
piperidine derivatives was demonstrated by a simple prepa-
ration of (()-senepodine G and (()-cermizine C (Scheme 2).
Isolated from the club moss of Lycopodium chinese, senepo-
dine G shows cytotoxicity against murine lymphoma L1210
cells with an IC50 of 7.8 μg/mL.6 To carry the synthesis forward,
the 1,4-addition product 1 was protected (Scheme 2) as the
ketal. Catalytic hydrogenation delivered a 1:1 ratio of the dia-
stereomers 9 and 10 that it was possible to separate by chro-
matography. Separately, exposure of each diastereomer to
acid gave the unstable alkaloids (()-senepodine G and (()-
3-(Pyridin-2-ylmethyl)cyclohexanone (2). To a stirred solution
of 2-picoline (392 mg, 4.2 mmol) in THF (4 mL) was added
n-BuLi (4.18 mmol, 2 mL, 2.09 M in hexane) at -78 °C. After
being stirred at 0 °C for 1 h, the reaction mixture was cooled to
-30 °C and added over 2 min to a stirred suspension of CuBr
3
SMe2 (415 mg, 2.02 mmol) in THF (4 mL) at -30 °C. After being
stirred for 2 h at -30 °C, the reaction mixture was cooled to -78 °C,
and a solution of 2-cyclohexenone (91 mg, 0.95 mmol) in THF
(3 mL) was added over 5 min. After being stirred at -78 °C for 2 h,
the reaction mixture was quenched with water (5 mL) and parti-
tioned between CH2Cl2 and, sequentially, water and brine. The
combined organic extract was dried (Na2SO4) and concentrated.
The residue was chromatographed to yield ketone 2 (142 mg, 79%
yield) as a pale yellow oil: TLC Rf (20% MTBE/CH2Cl2)=0.29;
IR (cm-1) 2935, 1706, 1592, 1457; 1H NMR δ 8.50 (app s, 1H),
(6) (a) Morita, H.; Hirasawa, Y.; Shinzato, T.; Kobayashi, J. Tetrahedron
2004, 60, 7015–7023. (b) Nishikawa, Y.; Kitajima, M.; Kogure, N.; Takayama,
H. Tetrahedron 2009, 65, 1608–1617. (c) Cui, L.; Peng, Y.; Zhang, L. J. Am.
Chem. Soc. 2009, 131, 8394–8395.
(7) Snider, B. B.; Grabowski, J. F. J. Org. Chem. 2007, 72, 1039–1042.
5738 J. Org. Chem. Vol. 75, No. 16, 2010

Taber et al.
JOCNote
7.55 (t, J= 7.9 Hz, 1H), 7.05 (m, 2H), 2.75 (m, 2H), 2.40-2.15
(m, 4H), 2.05 (m, 2H), 1.85 (m, 1H), 1.60 (m, 1H), 1.40 (m, 1H);
13C NMR δ u8 211.4, 159.5, 47.6, 45.1, 41.4, 31.1, 25.0; d 149.4,
136.3, 123.6, 121.4, 39.6; HRMS calcd for C12H16NO (MHþ)
190.1232, obsd 190.1237.
1H), 2.60 (m, 2H), 1.85-1.55 (m, 5H), 1.55-1.40 (m, 5H), 1.25
(s, 3H), 1.10 (m, 2H), 0.95 (d, J = 6.2 Hz, 3H); 13C NMR
(CD3OD) δ u 111.4, 65.4, 65.3, 47.6, 47.0, 46.5, 33.7, 26.7, 25.7; d
55.4, 26.2, 24.5, 21.8; HRMS calcd for C13H26NO2 (MHþ)
228.1964, obsd 228.1961.
4-Methyl-5-(pyridin-2-yl)pentan-2-one (1). To a stirred solu-
tion of 2-picoline (399 mg, 4.29 mmol) in THF (4 mL) was added
n-BuLi (4.19 mmol, 1.8 mL, 2.33 M in hexane) at -78 °C. After
being stirred at 0 °C for 1 h, the reaction mixture was cooled to
(()-Cermizine C TFA Salt (13). To a stirred solution of piperi-
dine 9 (46 mg, 0.20 mmol) in MeOH (1 mL) was added HCl (3 M,
1 mL) at room temperature. After being stirred at room tempe-
rature overnight, the reaction mixture was concentrated, includ-
ing high vacuum pumping, to give crude (()-senepodine G (11).
To a stirred solution of the above crude (()-senepodine G in
MeOH (4 mL) was added NaBH4 (20 mg, 0.52 mmol) at 0 °C.
After being stirred at room temperature for 10 min, the reaction
mixture was quenched with HCl (3 M, 2 mL) and then parti-
tioned between CH2Cl2 and, sequentially, water and brine. The
combined organic extract was dried (Na2SO4) and concentrated.
The residue was chromatographed to yield (()-cermizine C (13)
(27 mg, 80% yield) as a pale yellow oil: TLC Rf (Et2O saturated
with NH4OH) = 0.60. To a solution of the (()-cermizine C in
MeOH (0.5 mL) was added TFA5b,5c (1 drop, 20 μL, excess).
The mixture was concentrated to give (()-cermizine C TFA salt
-30 °C and added over 2 min to a stirred suspension of CuBr
3
SMe2 (425 mg, 2.06 mmol) in THF (4 mL) at -30 °C. After being
stirred for 2 h at -30 °C, the reaction mixture was cooled to -78 °C,
and a solution of 3-penten-2-one (90%, 102 mg, 1.09 mmol) in
THF (3 mL) was added over 5 min. After being stirred at -78 °C
for 2 h, the reaction mixture was quenched with water (5 mL)
and partitioned between CH2Cl2 and, sequentially, water and
brine. The combined organic extract was dried (Na2SO4) and
concentrated. The residue was chromatographed to yield ketone 1
(87 mg, 45% yield) as a pale yellow oil: TLC Rf (20% MTBE/
CH2Cl2)=0.33; IR (cm-1) 1704, 1647, 1367; 1H NMR δ 8.50 (app
s, 1H), 7.55 (m, 1H), 7.10 (m, 2H), 2.65 (m, 2H), 2.50 (m, 2H), 2.25
(m, 1H), 2.05 (s, 3H), 0.90 (d, J=6.6 Hz, 3H); 13C NMR δ u 208.7,
160.5, 50.3, 45.3; d 149.2, 136.3, 123.7, 121.2, 30.4, 30.2, 19.9;
HRMS calcd for C11H16NO (MHþ) 178.1232, obsd 178.1239.
2-(2-Methyl-3-(2-methyl-1,3-dioxolan-2- yl)propyl)pyridine (8).
To a stirred solution of ketone 1 (910 mg, 5.14 mmol) in benzene
(20 mL) were added p-toluenesulfonic acid monohydrate (120 mg,
0.60 mmol) and ethylene glycol (1.07 g, 17.3 mmol) at room tem-
perature. The reaction mixture was stirred at reflux overnight
with a Dean-Stark trap. After being cooled to room tempera-
ture, the reaction mixture was quenched with saturated aqueous
NaHCO3 (100 mL) and then partitioned between CH2Cl2 and,
sequentially, water and brine. The combined organic extract was
dried (Na2SO4) and concentrated. The residue was chromato-
graphed to yield ketal 8 (906 mg, 80% yield) as a pale yellow oil:
TLC Rf (20% MTBE/CH2Cl2) = 0.29; IR (cm-1) 2926, 1591,
1472, 1436; 1H NMR δ 8.50 (d, J=4.71 Hz, 1H), 7.55 (m, 1H),
7.05 (m, 2H), 3.90 (m, 4H), 2.85 (m, 1H), 2.55 (m, 1H), 2.20 (m,
1H), 1.70 (m, 1H), 1.55 (m, 1H), 1.30 (s, 3H), 0.95 (d, J=6.65 Hz,
3H); 13C NMR δ u 161.2, 110.3, 64.4, 64.2, 46.6, 44.9; d 149.2,
136.0, 123.6, 120.9, 30.2, 24.0, 20.7; HRMS calcd for C13H20-
NO2 (MHþ) 222.1494, obsd 222.1494.
1
as a yellow oil: IR (cm-1) 2524, 1675, 1455, 1201; H NMR
(CD3OD) δ 3.80 (m, 1H), 3.60 (m, 2H), 3.05 (m, 1H), 2.15 (m,
1H), 2.00-1.50 (m, 9H), 1.40-1.20 (m, 1H), 1.30 (d, J=6.4 Hz,
3H), 0.95 (d, J=6.4 Hz, 3H); 13C NMR (CD3OD) δ u 49.9, 41.8,
38.4, 24.6, 23.8, 18.4; d 61.4, 51.1, 25.5, 21.6, 17.6; HRMS calcd
for C11H22N (MHþ) 168.1752, obsd 168.1755.
(()-epi-Cermizine C TFA Salt (14). To a stirred solution of
piperidine 10 (40 mg, 0.18 mmol) in MeOH (1 mL) was added
HCl (3 M, 1 mL) at room temperature. After being stirred at
room temperature overnight, the reaction mixture was concen-
trated, including high vacuum pumping, to give crude (()-epi-
senepodine G (12).
To a stirred solution of the above crude (()-epi-senepodine G
in MeOH (4 mL) was added NaBH4 (15 mg, 0.39 mmol) at 0 °C.
After being stirred at room temperature for 10 min, the reaction
mixture was quenched with HCl (3 M, 2 mL) and then parti-
tioned between CH2Cl2 and, sequentially, water and brine. The
combined organic extract was dried (Na2SO4) and concen-
trated. The residue was chromatographed to yield (()-epi-
cermizine C (14) (23 mg, 78% yield) as a pale yellow oil: TLC
Rf (Et2O saturated with NH4OH) = 0.78. To a solution of the
(()-epi-cermizine C in MeOH (0.5 mL) was added TFA5b,5c
(1 drop, 20 μL, excess). The mixture was concentrated to give
(()-epi-cermizine C TFA salt as a yellow oil: IR (cm-1) 2529,
1665, 1198; 1H NMR (CD3OD) δ 3.75 (m, 1H), 3.20-3.00 (m,
2H), 2.70 (m, 1H), 2.00-1.65 (m, 7H), 1.55 (m, 2H), 1.40-1.20
(2S*)-2-((2S*)-Methyl-3-(2-methyl-1,3-dioxolan-2-yl)propyl)-
piperidine (9) and (2R*)-2-((2S*)-Methyl-3-(2-methyl-1,3-dioxo-
lan-2-yl)propyl)piperidine (10). A suspension of ketal 8 (350 mg,
1.58 mmol) and PtO2 (30 mg) in CH2Cl2 (3 mL) was stirred at
room temperature under H2 (1 atm) overnight. The reaction mix-
ture was filtered and concentrated. The residue was chromato-
graphed to yield amine 9 (172 mg, 48% yield) as a pale yellow oil
and amine 10 (170 mg, 47% yield) as a pale yellow oil.
(m, 2H), 1.35 (d, J=6.40 Hz, 3H), 0.95 (d, J=6.40 Hz, 3H); 13
C
NMR (CD3OD) δ u 51.9, 41.8, 40.4, 32.2, 24.9, 23.2; d 65.4, 62.4,
30.0, 21.4, 17.9; HRMS calcd for C11H22N (MHþ) 168.1752,
obsd 168.1752.
Piperidine 9: TLC Rf (10% Et2NH/PE) = 0.43; IR (cm-1
)
2929, 1646, 1450; 1H NMR (CD3OD) δ 3.90 (m, 4H), 3.05 (m,
1H), 2.60 (m, 2H), 1.85-1.55 (m, 5H), 1.55-1.40 (m, 5H), 1.30
(s, 3H), 1.25-1.0 (m, 2H), 0.95 (d, J = 6.6 Hz,3H); 13C NMR
(CD3OD) δ u 111.3, 65.4, 65.3, 47.4, 46.5, 45.8, 32.6, 26.4, 25.4; d
55.4, 26.1, 24.5, 22.2; HRMS calcd for C13H26NO2 (MHþ)
228.1964, obsd 228.1961.
Acknowledgment. We thank John Dykins for high-
resolution mass spectrometry under the financial support of
NSF 054117. NMR spectra were acquired with instrumenta-
tion supported by NSF CRIF:MU, CHE 080401. We thank
the NIH (GM060287) for financial support of this work.
Piperidine 10: TLC Rf (10% Et2NH/PE) = 0.49; IR (cm-1
)
2929, 1646, 1450; 1H NMR (CD3OD) δ 3.90 (m, 4H), 3.00 (m,
Supporting Information Available: General experimental
procedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(8) 13C multiplicities were determined with the aid of a JVERT pulse
sequence, differentiating the signals for methyl and methine carbons as “d”
and for methylene and quaternary carbons as “u”.
J. Org. Chem. Vol. 75, No. 16, 2010 5739