The Synthesis of 5,5-Disubstituted Piperidinones via a Reductive Amination-Lactamization Sequence: The Formal Synthesis of (±)-Quebrachamine

Article abstract of DOI:10.1055/s-0034-1379986

A preliminary investigation into the prospect of a common synthetic intermediate for the synthesis of a variety of indole alkaloids has led to a synthesis of substituted piperidinones and the corresponding piperidines. These common natural product cores a

Full text of DOI:10.1055/s-0034-1379986

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 815–819
letter
815
H. K. Grover, M. A. Kerr
Letter
Synlett
The Synthesis of 5,5-Disubstituted Piperidinones via a Reductive
Amination–Lactamization Sequence: The Formal Synthesis of
(±)-Quebrachamine
Huck K. Grover
O
Michael A. Kerr*
CHO
R
N
N
HN
RNH2
Department of Chemistry, The University of Western
Ontario, London, ON, N6A 5B7, Canada
makerr@uwo.ca
Et
[H]
MeO2C
CO2Me
N
H
NH
quebrachamine
R
R = CO2Me, CH2OH
Received: 08.10.2014
Accepted after revision: 18.12.2014
Published online: 05.02.2015
core 3 of a variety of alkaloid natural products (Scheme 1).
Herein, we report our initial findings on the utility of inter-
mediate 2 and the formal synthesis of quebrachamine.
DOI: 10.1055/s-0034-1379986; Art ID: st-2014-r0845-l
Abstract A preliminary investigation into the prospect of a common
synthetic intermediate for the synthesis of a variety of indole alkaloids
has led to a synthesis of substituted piperidinones and the correspond-
ing piperidines. These common natural product cores are accessed via a
reductive amination–lactamization sequence of dimethyl 3-ethyl-3-
formylpimelate. The synthetic utility of this initial study has been dis-
played in the formal synthesis of (±)-quebrachamine.
O
1) excess methyl
acrylate, MeOH
R
N
RNH2
[H]
N
CHO
2) AcOH, H2O
MeO2C
CO2Me
1
MeO2C
2 (54%)
Key words natural product, alkaloid, quebrachamine, heterocycles,
3
piperidine
Scheme 1 Synthesis and reactivity of 2
Nitrogen-containing heterocycles are a vital moiety
found in a variety of different natural and bioactive mole-
cules. In particular, piperidine natural products have re-
ceived much attention as target molecules for total synthe-
sis as well as ideal candidates for biological testing.1 Among
the vast array of piperidine natural products, our focus has
recently been drawn to the common core structure of the
Kopsia, Vinca, and Leuconotis alkaloids (Figure 1).2 In con-
tinuing efforts towards the synthesis of complex alkaloid
targets, we envisioned that the unique 3,3-disubstituted
piperidine pattern of this set of molecules could be pre-
pared via a common intermediate thus allowing rapid syn-
theses of these compounds from simple starting materials.3
While exploring a unified approach to these target mol-
ecules, we initially came across diester 2 (Scheme 1) which
contained the quaternary center features of the alkaloid
natural products. In fact, this molecule, prepared from
enamine 1 and two equivalents of methyl acrylate, has al-
ready been shown to be a versatile intermediate in many
different organic transformations.4 After extensive evalua-
tion of this compound, we envisioned it could be used as a
common starting material for preparation of the piperidine
A quick optimization varying solvent, temperature, and
reducing agents led to facile synthesis of piperidinone 3 in
excellent overall yield via a one-pot scandium triflate cata-
lyzed imine formation followed by a sodium borohydride
induced reductive lactamization sequence. Although it was
found that imine formation was possible in the absence of
the catalytic Lewis acid, the reaction times were signifi-
O
R
N
N
N
HN
O
O
R = CHO: rhazinal
R = H: rhazinilam
leuconoxine
O
N
N
CO2Me
leucomidine C
Figure 1 Piperidine-containing natural products
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 815–819

816
H. K. Grover, M. A. Kerr
Letter
Synlett
O
cantly increased and yields decreased when no catalytic ad-
ditive was used. In comparison to similar reductive amina-
tion–lactamization protocols reported in the literature,4b,c,5
the use of standard protic acids to prompt the initial imine
formation resulted in diminished yields (up to 57%), in-
creased reaction times, and incomplete starting material
conversion in our hands. The use of Sc(OTf)3 represents a
significantly beneficial modification to existing methods.
Standard reductive amination conditions using sodium cya-
noborohydride proved to be less efficient than sodium bo-
rohydride resulting in large amounts of recovered starting
materials. With ideal conditions in hand, we set out to de-
termine the scope of amines suitable for this transforma-
tion.
RNH2, Sc(OTf)3
MeOH
CHO
R
N
MeO2C
CO2Me
then
NaBH4
MeO2C
2
O
N
3a–i
O
N
O
TBSO
N
NH
NBoc
MeO2C
MeO2C
MeO2C
3a: 96%
3b: 76%
3c: 76%
Tryptamine derivatives were quite compatible with the
reaction conditions leading to 3a and 3b in good to excel-
lent yields (Scheme 2).14 These results were particularly in-
teresting as they allowed quick access to the indole skeleton
prevalent in several target alkaloid molecules.6 Protected
ethanolamine underwent the transformation giving access
to 3c in 76% yield while 2-(phenylthio)ethanol led to 3d in a
moderate 64% yield. The future utility of these two com-
pounds (3c and 3d) was noteworthy as their functional
handles allowed for easy manipulation to more complex
scaffolding as seen in several previous alkaloid syntheses.7
Additionally, benzylamine was suitable as a starting materi-
al giving 3e as protected piperidinone in good yield. This
particular reaction was amenable to scale up. Butylamine
worked well giving high yields of the desired product 3f;
however, when cyclohexylamine was employed, lower
yields of the desired product 3i were isolated. This was pre-
sumably due to steric effects between the bulky amine and
the neopentyl aldehyde resulting in lower formation of the
requisite imine. This hypothesis was further supported
when tert-butylamine proved unreactive toward 2 under
the reaction conditions. p-Methoxyaniline was shown to
undergo the reaction with 2; however, in the best case, only
31% yield of 3g could be isolated. This low yield could be at-
tributed to the slow lactam-formation step of the reaction
process since significant amounts of the simple reductive
amination product were also isolated. Attempts to modify
the reaction conditions (including variations in tempera-
ture) proved unsuccessful in increasing the overall yield for
anilines. Finally, allylamine successfully led to 3h in an 83%
yield providing another useful handle for future manipula-
tions.
O
O
O
PhS
N
Ph
N
N
MeO2C
MeO2C
MeO2C
3d: 64%
3e: 81%
3f: 86%
MeO
O
O
O
N
N
N
MeO2C
MeO2C
MeO2C
3g: 31%a
3h: 83%
3i: 40%
Scheme 2 Reaction scope. Reagents and conditions: amine (1 equiv), 2
(1 equiv), Sc(OTf)3 (2.5 mol%), NaBH4 (1.25 equiv). a Reaction gave 3g
plus reductive amination product as the major product.
(Scheme 3, 4a–c). This result allowed quick access to ideal
functional handles on the 3-position of the piperidine core
without loss of yield or extraneous purification.
If necessary, a two-step piperidinone ring formation es-
ter reduction protocol could be applied allowing access to
the corresponding (3-hydroxypropyl)piperidinone in excel-
lent yields (Scheme 4).9 Finally, the piperidine ring system
can be accessed through a Red-Al®-mediated lactam–ester
reduction (Scheme 4). Piperidinone 3c containing the TBS
O
In addition to amine substitution, the ester moiety of
the product can also be manipulated in a one-pot sequence
(Scheme 3). When the reaction conditions were adjusted to
use excess sodium borohydride in refluxing methanol, the
corresponding (3-hydroxypropyl)piperidinones were iso-
lated as the sole product.8 Interestingly, when compared to
the initial reaction conditions (Scheme 2, 3c–e), there was
little to no effect on the overall yield of product although
and additional reduction event was added to the sequence
CHO
RNH2, Sc(OTf)3
MeOH, r.t.
R
N
MeO2C
CO2Me
HO
then
excess NaBH4
reflux
2
4a R = (CH2)2OTBS, 72%
4b R = (CH2)2SPh, 60%
4c R = Bn, 81%
Scheme 3 One-pot ester reduction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 815–819

817
H. K. Grover, M. A. Kerr
Letter
Synlett
ether gave piperidine 5a in 72% yield while benzyl-protect-
ed 3e gave 5b in a nearly quantitative yield. The decrease in
yield seen for 5a could be attributed to the in situ desilyla-
tion of the product under the reaction conditions.
O
CHO
H2N
Ph
BnN
MeO2C
CO2Me
MeOH, NaBH4
81%
HO
2
4c
O
O
Red-Al®
THF
0 °C to r.t.
NaBH4
MeOH
reflux
R
R
R
N
N
N
IBX, EtOAc
82%
HO
HO
MeO2C
O
O
P
3c–e
4a R = (CH2)2OTBS, 99%
4b R = (CH2)2SPh, 100%
4c R = Bn, 100%
5a R = (CH2)2OTBS, 72%
5b R = Bn, 98%
O
O
OMe
OMe
BnN
BnN
N2
Scheme 4 Reduction conditions for the synthesis of 4a–c and 5a,b
O
MeOH, K2CO3
97%
8
7
To display the utility of this transformation, the indole
alkaloid (±)-quebrachamine (6) was targeted for synthesis.
Belonging to the Aspidosperma alkaloid family, quebra-
chamine was isolated over a century ago from the bark of
the Aspidosperma quebracho-blanco tree along with several
other structurally similar alkaloids (Figure 2).10 This family
of natural products exhibit a large array of biological activi-
ty and due to the incorporation of the piperidine ring, this
molecule serves as the perfect model for this transforma-
tion.11
2-iodoaniline
PdCl2(PPh3)2, CuI
Et3N, THF
93%
O
O
BnN
BnN
ZnI2
toluene
100%
9
NH
10
N
NH2
Red-Al®
THF
N
H
97%
quebrachamine (6)
Pd/C, NH4CO2
MeOH, reflux
84%
HN
BnN
Figure 2 (±)-Quebrachamine
Starting from readily available dimethyl 3-ethyl-3-
formylpimelate, a one-pot global reductive amination–lact-
amization protocol was employed with benzyl amine lead-
ing to piperidinone 4c in an 81% yield (Scheme 5). Oxida-
tion of the corresponding primary alcohol with IBX gave al-
dehyde 7 without purification. Homologation of 7 with the
Bestmann–Ohira reagent led to alkyne 8 in an excellent
yield. Next, the alkyne was subjected to a two-step cross-
coupling hydroamination protocol to furnish indole 10.12
With the indole core in hand, reduction of the lactam with
Red-Al®-supplied benzyl-protected piperidine 11 in an ex-
ceptional 97% yield. Final deprotection of the benzyl group
gave 12 which constitutes a formal total synthesis of que-
brachamine since 12 was transformed into the target in a
three-step procedure developed by Pagenkopf in 2009.13
In conclusion, our initial investigation into a unified ap-
proach toward the piperidine-containing alkaloid natural
products has proved successful. Common starting material
2 has been applied in the synthesis of a variety of N-substi-
NH
Scheme 5 Formal synthesis of quebrachamine
NH
12
11
tuted piperidinone scaffolds via a reductive animation–lac-
tamization sequence, and this process has been applied to
the short formal synthesis of indole alkaloid (±)-quebra-
chamine. These preliminary findings show great promise
for the use of more complex derivatives in the synthesis of a
series of nitrogen-containing natural products. New direc-
tions for this research area are currently under investiga-
tion within our laboratory.
Acknowledgment
We thank the Natural Sciences and Engineering Research Council of
Canada for generous funding of this research. We are grateful to Mr.
Doug Hairsine of the Western University Mass Spectrometry facility
for performing MS analyses.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 815–819

818
H. K. Grover, M. A. Kerr
Letter
Synlett
Supporting Information
(12) All attempts at a one-pot Larock-type indole synthesis resulted
in significantly lower yields of the desired product. In most
cases increased reaction times were required.
(13) Bajtos, B.; Pagenkopf, B. Eur. J. Org. Chem. 2009, 1072.
(14) General Experimental Procedure for the Synthesis of Piper-
idinones 3a–i
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379986.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
Compound 2 (1 equiv) and primary amine (1 equiv) were dis-
solved in MeOH. Sc(OTf)3 (0.025 equiv) was then added, and the
mixture was stirred for 1–2 h, followed by the addition of
NaBH4 (1.25 equiv). Upon completion by TLC analysis H2O was
added to the reaction mixture and extracted 3 times with
EtOAc. The organic layer was dried, and the solvent was
removed. The residue was purified by flash chromatography
(EtOAc–hexanes) to yield the desired piperidinones 3a–i.
Piperidinone 3c
(1) Selected recently total synthesis of piperidine containing target
molecules: (a) Ghavimi, B.; Mangus, P. Org. Lett. 2014, 16, 1708.
(b) Bradshaw, B.; Luque-Corredera, C.; Bonjoch, J. Chem.
Commun. 2014, 50, 7099. (c) Teng, M.; Zi, W.; Ma, D. Angew.
Chem. Int. Ed. 2014, 53, 1814. (d) Itoh, N.; Iwata, T.; Sugihara, H.;
Inagaki, F.; Mukai, C. Chem. Eur. J. 2013, 19, 8665. (e) Kress, S.;
Weckesser, J.; Schulz, S.; Blechert, S. Eur. J. Org. Chem. 2013,
1346.
(2) (a) Kam, T. S.; Tee, Y. M.; Subramaniam, G. Nat. Prod. Lett. 1998,
12, 307. (b) Abe, F.; Yamauchi, T. Phytochemistry 1994, 35, 169.
(c) Linde, H. Helv. Chim. Acta 1965, 48, 1822. (d) Abraham, D.;
Rosenstein, R.; Lyon, R.; Fong, H. Tetrahedron Lett. 1972, 13, 909.
(e) Motegi, M.; Nugroho, A.; Hirasawa, Y.; Arai, T.; Hadi, A.;
Morita, H. Tetrahedron Lett. 2012, 53, 1227.
(3) (a) Karadoelian, A.; Kerr, M. Angew. Chem. Int. Ed. 2010, 49,
1133. (b) Carson, C.; Kerr, M. Org. Lett. 2009, 11, 777. (c) Leduc,
A.; Kerr, M. Angew. Chem. Int. Ed. 2008, 47, 7945. (d) Magolan, J.;
Carson, C.; Kerr, M. Org. Lett. 2008, 10, 1437. (e) Johansen, M.;
Leduc, A.; Kerr, M. Synlett 2007, 2593. (f) Young, I.; Kerr, M. J.
Am. Chem. Soc. 2007, 129, 1465. (g) Leduc, A.; Kerr, M. Eur. J. Org.
Chem. 2007, 2, 237. (h) Carson, C.; Kerr, M. Angew. Chem. Int. Ed.
2006, 45, 6560.
(4) (a) Nemes, A.; Szantay, C.; Czibula, L.; Greiner, I. ARKIVOC 2008,
154. (b) Amat, M.; Bassas, O.; Llor, N.; Canto, M.; Perez, M.;
Molins, E.; Bosch, J. Chem. Eur. J. 2006, 12, 7672. (c) Amat, M.;
Canto, M.; Llor, N.; Ponzo, V.; Perez, M.; Bosch, J. Angew. Chem.
Int. Ed. 2002, 21, 335. (d) Szabo, L.; Szentirmay, E.; Baitz-Gacs,
E.; Kalaus, G.; Szantay, C. Tetrahedron Lett. 1997, 38, 115.
(e) Alazard, J.-P.; Terrier, C.; Thal, C. Tetrahedron 1994, 50, 6287.
(f) Carite, C.; Alazard, J.-P.; Ogino, K.; Thal, C. Tetrahedron Lett.
1990, 31, 7011. (g) Castedo, L.; Harley-Mason, J.; Kaplan, M.
Chem. Commun. 1969, 1444. (h) Kuehne, M. J. Am. Chem. Soc.
1964, 86, 2946.
Yellow oil, 76% yield (346 mg, 0.93 mmol). Rf = 0.27, EtOAc. 1H
NMR (600 MHz, CDCl3): δ = 3.76 (dd, J = 5.9, 5.9 Hz, 2 H), 3.67 (s,
3 H), 3.49–3.40 (m, 2 H), 3.18 (AB system, 2 H), 2.35 (dd, J = 7.0,
7.0 Hz, 2 H), 2.25–2.22 (m, 2 H), 1.75–1.66 (m, 2 H), 1.63–1.55
(m, 2 H), 1.44–1.38 (m, 1 H), 1.36–1.30 (m, 1 H), 0.89 (s, 9 H),
0.84 (t, J = 7.3 Hz, 3 H), 0.05 (s, 6 H). 13C NMR (150 MHz, CDCl3):
δ = 173.8, 169.6, 61.6, 58.9, 51.7, 50.5, 34.5, 29.7, 28.9, 28.5,
28.3, 26.9, 25.8, 18.1, 7.4, –5.5. IR (thin film): 2930, 2858, 1740,
1646, 1493, 1470, 1436, 1363, 1256, 1105, 1054, 1006, 921, 837,
778 cm–1. HRMS: m/z calcd for C19H37NO4Si [M + 1]: 372.2565;
found: 372.2565.
Piperidinone 3e
Orange oil, 81% yield (202 mg, 0.67 mmol). Rf = 0.28, EtOAc.
1H NMR (600 MHz, CDCl3): δ = 7.32–7.30 (m, 2 H), 7.27–7.24
(m, 3 H), 4.57 (AB system, 2 H), 3.65 (s, 3 H), 2.91 (AB system, 2
H), 2.46 (dd, J = 7.0, 1.2 Hz, 2 H), 2.18–2.12 (m, 1 H), 2.04–1.98
(m, 1 H), 1.63–1.59 (m, 4 H), 1.33–1.22 (m, 2 H), 0.71 (t, J = 7.6
Hz, 3 H). 13C NMR (150 MHz, CDCl3): δ = 173.7, 169.5, 137.1,
128.6, 128.3, 127.5, 55.4, 51.7, 50.3, 34.3, 30.0, 28.9, 28.5, 28.2,
26.5, 7.2. IR (thin film): 3454, 3056, 3062, 3029, 2948, 1736,
1647, 1494, 1454, 1363, 1229, 1069, 1002, 854, 703 cm–1
.
HRMS: m/z calcd for
C18H25NO3 [M]: 303.1834; found:
303.1825.
General Experimental Procedure for the Synthesis of 5-(3-
Hydroxypropyl)piperidin-2-one 4a–c
Procedure 1
(5) (a) Laronze, P.; Laronze-Fontaine, J.; Levy, J.; Le Men, J. Tetrahe-
dron Lett. 1974, 491. (b) Giri, V.; Ali, E.; Parkashi, S. J. Heterocycl.
Chem. 1980, 17, 1133.
Piperidinone (1 equiv) was dissolved in MeOH, followed by the
addition of NaBH4 (5 equiv). The mixture was heated to reflux
for 10 min and then cooled to r.t. Then additional NaBH4 (5
equiv) was added followed by a 10 min reflux period, this
process was continued until a total of 40 equiv NaBH4 was
added. Upon complete addition of NaBH4, H2O was slowly added
to the reaction mixture and extracted 3 times with EtOAc. The
organic layer was dried, and the solvent was removed. The
residue was purified by flash chromatography (EtOAc–hexanes)
to yield the desired piperidinones 4a–c.
(6) For selected examples of indole alkaloids, see: (a) Smith, G.;
Wahid, M. J. Chem. Soc. 1963, 4002. (b) Hava, H. The Vinca Alka-
loids; Taylor, W.; Farnsworth, N., Eds.; Marcel Dekker: New York,
1973, Chap. 6. (c) Rahman, A.; Malik, S. J. Nat. Prod. 1985, 48,
153. (d) Lim, K.-H.; Kam, T.-S. Helv. Chim. Acta 2007, 90, 31.
(7) For selected uses in synthesis, see: (a) Desmaele, D.; D’Angelo, J.
Tetrahedron Lett. 1990, 31, 883. (b) Desmaele, D.; D’Angelo, J. J.
Org. Chem. 1994, 59, 2292. (c) Magnus, P.; Brown, P. J. Chem.
Soc., Chem. Commun. 1985, 184.
(8) Sequential additions of sodium borohydride in between reflux
periods are required to ensure complete conversion. See experi-
mental for details.
(9) Excess sodium borohydride is used. See experimental for details.
(10) Hesse, O. Ber. Dtsch. Chem. Ges. 1881, 13, 2308.
Procedure 2
Dimethyl 3-ethyl-3-formylpimelate (1 equiv) and primary
amine (1 equiv) were dissolved in MeOH. Sc(OTf)3 (0.025 equiv)
was then added, and the mixture was stirred for 1–2 h, followed
by the addition of NaBH4 (5 equiv). The mixture was heated to
reflux for 10 min and then cooled to r.t. Then additional NaBH4
(5 equiv) was added followed by a 10 min reflux period, this
process was continued until a total of 40 equiv NaBH4 was
added. Upon complete addition of NaBH4, H2O was slowly
added to the reaction mixture and extracted 3 times with
EtOAc. The organic layer was dried and the solvent was
(11) (a) Joule, J. The Alkaloids; Vol. 1; Saxton, J., Ed.; The Chemical
Society: London, 1971, 178. (b) Deutsch, H.; Evenson, M.;
Drescher, P.; Sparwasser, C.; Madsen, P. J. Pharm. Biomed. Anal.
1994, 12, 1283.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 815–819

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H. K. Grover, M. A. Kerr
Letter
Synlett
removed. The residue was purified by flash chromatography
(EtOAc–hexanes) to yield the desired piperidinones 4a–c.
5-(3-Hydroxypropyl)piperidin-2-one 4a
1308, 1229, 1067, 1028, 703 cm–1
.
HRMS: m/z calcd for
C
17H25NO2 [M]: 275.1885; found: 275.1880.
General Experimental Procedure for the Synthesis of Piperi-
dines 5a,b
Thick yellow oil, 99% yield (630 mg, 1.81 mmol). Rf = 0.14,
EtOAc. 1H NMR (600 MHz, CDCl3): δ = 3.71 (dd, J = 5.3, 5.3 Hz, 2
H), 3.56 (dd, J = 5.9, 5.9 Hz, 2 H), 3.46–3.42 (m, 1 H), 3.37–3.33
(m, 1 H), 3.14 (AB system, 2 H), 2.47 (br s, 1 H), 2.29 (dd, J = 7.0,
7.0 Hz, 2 H), 1.55 (dd, J = 7.0, 7.0 Hz, 2 H), 1.46–1.34 (m, 4),
1.33–1.26 (m, 2 H), 0.84 (s, 9 H), 0.79 (t, J = 7.6 Hz, 3 H), 0.00 (s,
6 H). 13C NMR (150 MHz, CDCl3): δ = 170.1, 62.9, 61.4, 59.3, 50.5,
34.5, 30.0, 29.8, 28.5, 27.1, 26.2, 25.8, 18.1, 7.4, –5.5. IR (thin
film): 2930, 2858, 1626, 1497, 1464, 1418, 1362, 1255, 1101,
1058, 837, 778 cm–1. HRMS: m/z calcd for C18H37NO3Si [M + 1]:
344.2622; found: 344.2615.
Piperidinone (1 equiv) was dissolved in THF followed by the
addition of Red-Al® (65% by weight; 4 equiv). Upon completion
by TLC analysis H2O was added to the reaction mixture and
extracted 3 times with EtOAc. The organic layer was dried and
the solvent was removed. The residue was purified by flash
chromatography (EtOAc–hexanes) to yield the desired product
5a,b.
Piperidine 5a
Orange oil, 72% yield (160 mg, 0.49 mmol). Rf = 0.11, EtOAc.
1H NMR (600 MHz, CDCl3): δ = 3.71 (dd, J = 6.5, 6.5 Hz, 2 H), 3.61
(ddd, J = 6.5, 6.5, 2.3 Hz, 2 H), 2.51–2.39 (m, 3 H), 2.31–2.19 (m,
2 H), 2.08–2.04 (m, 1 H), 1.61–1.50 (m, 2 H), 1.49–1.37 (m, 3 H),
1.36–1.25 (m, 4 H), 1.20–1.16 (m, 1 H), 0.88 (s, 9 H), 0.77 (t, J =
7.0 Hz, 3 H), 0.05 (s, 6 H). 13C NMR (150 MHz, CDCl3): δ = 63.8,
63.6, 61.3, 61.2, 55.4, 35.3, 33.6, 28.3, 25.9, 21.9, 18.3, 7.3, 5.3
(missing 2 carbons, presumably due to overlap). IR (thin film):
2933, 2857, 1463, 1255, 1103, 1068, 836, 776 cm–1. HRMS: m/z
calcd for C18H39NO2Si [M]: 329.2750; found: 329.2754.
5-(3-Hydroxypropyl)piperidin-2-one 4c
Dark yellow oil, 100% yield (1459 mg, 5.30 mmol). Rf = 0.14,
EtOAc; 1H NMR (600 MHz, CDCl3): δ = 7.32–7.30 (m, 2 H), 7.27–
7.24 (m, 3 H), 4.55 (AB system, 2 H), 3.51 (dd, J = 5.9, 5.9 Hz, 2
H), 2.92 (AB system, 2 H), 2.43 (dd, J = 7.0, 7.0 Hz, 2 H), 1.62 (m,
3 H), 1.43–1.35 (m, 1 H), 1.34–1.16 (m, 5 H), 0.71 (t, J = 7.0 Hz, 3
H). 13C NMR (150 MHz, CDCl3): δ = 169.8, 137.3, 128.5, 128.3,
127.4, 63.1, 55.7, 50.3, 34.3, 30.2, 29.9, 28.5, 26.9, 26.2, 7.3. IR
(thin film): 3395, 2939, 2866, 1620, 1496, 1454, 1419, 1363,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 815–819

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