Nucleophilic additions of lactam-derived enol triflates to aldehydes mediated by nickel(II) and chromium(II) salts

Article abstract of DOI:10.1139/v03-164

Enol trifluoromethanesulfonates (triflates) derived from N-protected lactams undergo nickel(II)-chloride- and chromium(II)-chloride-promoted carbonyl additions to aldehydes. The yields of this process range from 42%-84%.

Full text of DOI:10.1139/v03-164

139
Nucleophilic additions of lactam-derived enol
triflates to aldehydes mediated by nickel(II) and
chromium(II) salts1
Leah P. Easton and Gregory R. Dake
Abstract: Enol trifluoromethanesulfonates (triflates) derived from N-protected lactams undergo nickel(II)-chloride- and
chromium(II)-chloride-promoted carbonyl additions to aldehydes. The yields of this process range from 42%–84%.
Key words: nickel(II) chloride, chromium(II) chloride, carbonyl addition, lactam-derived enol triflate.
Résumé : Sous l’influence du chlorure de nickel(II) ou du chlorure de chrome(II), les trifluorométhanesulfonates (tri-
flates) d’énol obtenus à partir de lactames N-protégés donnent lieu à des réactions d’addition de carbonyles avec for-
mation d’aldéhydes avec des rendements qui vont de 42% à 84%.
Mots clés : chlorure de nickel(II), chlorure de chrome(II), addition de carbonyle, triflate d’énol dérivé de lactames.
[Traduit par la Rédaction] Easton and Dake 144
Introduction
(4). Despite the growing use of lactam-derived enol triflates
as substrates for metal-promoted (or catalyzed) reactions (5),
we were unsure of the plausibility of our hypothesis. We are
aware, to the best of our knowledge, of no examples of
nickel(II)–chromium(II)-promoted carbonyl addition reac-
tions using lactam-derived enol triflates. Our successful in-
vestigations on the feasibility of this process are disclosed in
this report.
To investigate the use of semipinacol reactions for the
construction of alkaloid natural products (1), our group be-
came interested in the preparation of compounds such as A
(Scheme 1). Functionalized lactams appeared to be reason-
able starting materials for the preparation of compounds like
A. Currently we use a synthetic protocol that involves the
following: (a) conversion of the N-protected lactam to its
enol trifluoromethanesulfonate (triflate); (b) formation of a
vinylstannane from the enol triflate using a palladium(0)-
catalyzed coupling reaction; and (c) transmetalation of the
stannane to a more nucleophilic lithium or magnesium spe-
cies, which is reacted with a carbonyl compound. Although
this procedure works well and can be scaled up, it does have
drawbacks. Specifically, the requirement of hexamethyl-
distannane in the sequence is a liability because of its ex-
pense and toxicity (2).3 Because of the known facility of
mixtures of nickel(II) and chromium(II) salts in promoting
additions of vinyl halides or triflates to carbonyl compounds
(3), we were intrigued by the possibility of using such a pro-
cess on a triflate derived from a lactam, thus possibly re-
moving the need for hexamethyldistannane. A precedent for
this proposed transformation is the use of a lactone-derived
enol triflate in a nickel(II)–chromium(II) salt promoted alde-
hyde addition reaction, reported by Nicolaou and co-workers
Results and discussion
The known enol triflate 14 was selected to probe the
viability of the nickel(II)–chromium(II)-promoted carbonyl
addition. Enol triflate 1 was easily formed by deprotonating
N-tert-butoxycarbonyl-2-piperidone with lithium hexamethyl-
disilazide followed by enolate quenching with N-(5-chloro-
2-pyridyl)-triflimide. Unlike enol triflates derived from 5-
and 7-membered ring lactams, which can be difficult to store
and handle,5 1 can be purified by column chromatography
on silica gel and can be stored for weeks in the freezer. The
reaction between 1 and benzaldehyde, using a variety of dif-
ferent conditions, was initially explored (Scheme 2 and Ta-
ble 1).
A typical set of reaction conditions suitable for the
nickel(II)–chromium(II) carbonyl addition process were
Received 23 June 2003. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 9 January 2004.
This article is dedicated to my teacher, mentor, and colleague, Professor Edward Piers.
L.P. Easton and G.R. Dake.2 Department of Chemistry, 2036 Main Mall, University of British Columbia, Vancouver, BC
V6T 1Z1, Canada.
1This article is part of a Special Issue dedicated to Professor Ed Piers.
2Corresponding author (e-mail: gdake@chem.ubc.ca).
3The current cost for 5 g of hexamethyldistannane is Can$141.80 (Aldrich). The cost is even higher when one considers that only
one “trimethyltin” group is transferred, and the other is discarded.
4References 5(m) and 5(n).
5See, for example, ref. 5(f).
Can. J. Chem. 82: 139–144 (2004)
doi: 10.1139/V03-164
© 2004 NRC Canada

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Can. J. Chem. Vol. 82, 2004
Scheme 1.
Scheme 3.
Scheme 2.
Table 1. Optimization of addition of enol triflate 1 to benzaldehyde.
Entry
equiv. PhCHO
equiv. CrCl2
Solvent
Reaction parameter
Yield 2 (%)a
1
2
3
4
5
6
7
6
6
6
6
6
6
2
6
6
6
6
6
4
6
DMF–THF
DMSO–THF
DMSO
DMF
DMF
DMF
Sonication
Sonication
Sonication
Sonication
Stirring
60
10
26
66
50
27
63
Sonication
Sonication
DMF
aAfter isolation and purification.
used. Treatment of 1 with excess benzaldehyde (6 equiv), in
the presence of 6 equiv of chromium(II) chloride and
nickel(II) chloride (2 mol%), in a 1:1 mixture of degassed
DMF–THF mixture at room temperature for 15 h produced
the desired adduct 2 in 60% isolated yield (entry 1). The
structure of 2 was established by spectroscopic methods.
The IR spectrum of 2 contained absorptions typical of both
alcohol (3404 cm–1) and carbonyl (1682 cm–1) functional
groups. Key signals in the 1H NMR spectrum of 2 at
δ 5.35 ppm (d, J = 9.2 Hz, 1H) and δ 1.29 ppm (s, 9H) could
be attributed to the allylic methine proton and the protons on
the tert-butyl group. It is noteworthy that the alkoxide that is
presumably generated after the carbonyl addition does not
cyclize into the tert-butyl carbamate protecting group to
form an oxazolidinone (6).
The choice of solvent had a substantial effect on the course
of this reaction. For example, no reaction was observed to
take place when using THF as the sole solvent, and using a
1:1 mixture of degassed THF and DMSO produced 2 in only
10% yield (entry 2). Omitting the ether solvent and running
the reaction in DMSO alone improved the process somewhat
(26% yield of 2, entry 3). An amide solvent was clearly su-
perior, as running the reaction in DMF alone restored the
yield to acceptable levels, 66% (entry 4). Sonication
probably better disperses the chromium(II) chloride during
the reaction, compared with simple stirring (4). Using stir-
ring to agitate the reaction mixture in DMF resulted in a
lowered yield of 2 of 50% (entry 5). Unfortunately, the use
of a smaller amount of chromium(II) chloride (4 equiv) dras-
tically reduced the amount of adduct 2 that was isolated af-
ter reaction (27%, entry 6). In contrast, the use of a
substantial excess of benzaldehyde is not necessary. Adduct
2 was isolated in 63% yield when 2 equiv of benzaldehyde
was used with DMF as solvent (entry 7). These conditions
(using either 6 or 2 equiv of electrophile) were adapted as
our “standard protocol” for this process.
The effect of the different protecting groups on the nitro-
gen of the enol triflate nucleophile was then examined
(Scheme 3). Although the N-toluenesulfonyl derivative 3 did
react as a nucleophile using these reaction conditions, the ef-
ficiency of the reaction was much lower in comparison with
the reactions of 1. For example, the reaction of 3 with ben-
zaldehyde produced allylic alcohol 4 in 46% yield. Hexanal
could also be employed as an electrophile. Allylic alcohol 5
was isolated from the reaction of 3 and hexanal in 42%
yield. Attempts to use other common protecting groups for
© 2004 NRC Canada

Easton and Dake
141
the number of equivalents of chromium(II) salts would sub-
stantially improve this process. The lack of reactivity in
ethereal solvents is a second handicap that we have uncov-
ered. Although nitrogen-based ligand scaffolds have been
used to generate catalytic versions of this carbonyl-addition
reaction, those processes typically use THF as a solvent or
co-solvent (8). Our preliminary investigations have found
that no reaction occurs in THF, despite the presence of ex-
ternal ligands. Finally, the sonication of reaction mixtures is
much more easily performed on a small scale. An alternative
method for agitation would be required for large-scale reac-
tions. The convenient resolution of all of these issues would
generate a generally useful synthetic protocol.
Scheme 4.
Table 2. Addition of Boc-protected enol triflate 1 to various al-
dehydes.
equiv.
RCHO
Yield
Entry
1
R
Product
6
(%)a
42
6
Conclusion
2
3
4
6
6
6
7
8
9
49
84
76
Lactam-derived enol triflates have been demonstrated to
undergo nickel(II)–chromium(II) salt mediated carbonyl ad-
dition reactions with aldehydes to produce functionalized al-
lylic alcohols. Interestingly, reactions involving aliphatic
aldehydes are typically higher yielding compared with aro-
matic aldehydes. With the feasibility of this protocol estab-
lished, efforts to render this process catalytic in nickel and
chromium (9) and to apply this reaction in the construction
of nitrogen-containing natural products are underway in our
laboratories.
5
6
7
2
2
6
10
11
12
62
71
51
Experimental
aAfter isolation and purification.
General information
All reactions were carried out under a nitrogen atmo-
sphere in flame-dried glassware. Tetrahydrofuran was dis-
tilled from sodium, using benzophenone as an indicator.
Dimethyl sulfoxide was distilled from calcium hydride under
reduced pressure. Dimethyl formamide was dried over mo-
lecular sieves (4 Å) and degassed by sparging with nitrogen
gas. Commercially available aldehydes (Aldrich) were dis-
tilled over sodium sulfate under reduced pressure prior to
use. Nickel chloride (98%) was purchased from Aldrich and
chromium chloride (99.9%) was purchased from Strem.
Thin-layer chromatography (TLC) was performed on DC-
Fertigplatten SIL G-25 UV254 pre-coated TLC plates.
Sonication was carried out using a Branson 3200 sonicator.
Melting points were performed using a Mel-Temp II appara-
tus (lab devices U.S.A.) and are uncorrected. Infrared (IR)
spectra were obtained using a PerkinElmer 1710 FT-IR spec-
trometer. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded in deuterated chloroform, using a
Bruker WH-400 spectrometer. Carbon nuclear magnetic res-
onance (13C NMR) spectra were recorded in deuterated chlo-
roform, using a Bruker AV-300 spectrometer. Chemical
shifts (δ) are reported in parts per million (ppm) and are ref-
erenced to deuterated chloroform (δ 7.24 ppm 1H NMR;
δ 77.0 ppm 13C NMR). Low-resolution mass spectra (LR-
MS) were recorded using either a Kratos-AEI model MS 50
or an Aligent 6890 series GC with a 5973 MS. Microanaly-
ses were performed on either a Carlo Erba Elemental Ana-
lyzer Model 1106 or a CHN-O Elemental Analyzer Model
1108.
nitrogen, such as benzyloxycarbonyl (Cbz), trifluoromethan-
sulfonyl (Tf), or benzoyl, were complicated by either the in-
stability of the enol triflates or the formation of several
byproducts during the chromium(II)–nickel(II)-promoted
carbonyl addition process.
Using the standard conditions, a variety of aldehydes were
then reacted with 1 to probe the scope and limitations of the
electrophilic partner (Scheme 4 and Table 2). Electron-rich
aromatic aldehydes such as p-anisaldehyde (entry 1) or
furfural (entry 2) could be used in this reaction, although the
yields of the products 6 and 7 were modest: 42% and 49%,
respectively. Interestingly, aliphatic aldehydes react more ef-
fectively, and the carbonyl addition products could be iso-
lated in much higher yields. As examples, the reactions of 1
with hexanal and isopropanal, using the standard conditions,
resulted in the formation of allylic alcohols 8 and 9 in 84%
and 76% isolated yields, respectively (entries 3 and 4). Con-
sidering the previous use of the chromium(II)–nickel(II)-pro-
moted addition reaction in complex total synthesis (7), it
was not surprising that common organic functional groups
are compatible with these conditions. Functionalities such as
acetals (entry 5, 10, 62% yield), ethers (entry 6, 11, 71%
yield), and alkynes (entry 7, 12, 51% yield) were well toler-
ated in the reaction of 1 under these conditions. Interest-
ingly, attempts to react 1 with cinnamaldehyde were
unsuccessful because of problems with decomposition.
Although the desired transformation does occur, this pro-
cess has its own drawbacks. The first is the large amount of
chromium(II) chloride that is required for reaction. Reducing
© 2004 NRC Canada

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Can. J. Chem. Vol. 82, 2004
of THF was added. The mixture was allowed to warm to
25 °C. After 1 h the reaction was quenched with 5 mL of a
saturated aqueous ammonium chloride solution. The aque-
ous phase was extracted with three 4 mL portions of
dichloromethane. The combined extracts were dried over so-
dium sulfate, filtered, and concentrated via rotary evapora-
tion. Purification via flash chromatography (1:3 ethyl acetate –
hexanes, containing 1% triethylamine) on silica gel gave
195 mg (64%) of white crystals, mp 47 to 48 °C. IR (KBr)
(cm–1): 3436, 1674, 1425, 1362, 1213, 1173. 1H NMR
(400 MHz, CDCl3) δ: 7.75 (d, J = 8.24 Hz, 2H), 7.32 (d, J =
8.24 Hz, 2H), 5.43 (t, J = 3.97 Hz, 1H), 3.60–3.64 (m, 2H),
2.42 (s, 3H), 2.09–2.14 (m, 2H), 1.53–1.45 (m, 2H).
tert-Butyl 6-{[(trifluoromethyl)sulfonyl]oxy}-3,4-
dihydropyridine-1(2H)-carboxylate (1)
To a solution of 367 mg of 1,1,1,3,3,3-hexamethyldisila-
zane (2.27 mmol) in 3 mL of THF at –78 °C was added
1.57 mL of n-butyllithium in hexane (2.26 mmol, 1.44 mol L–1).
After stirring for 20 min, the mixture was transferred via
cannula to a solution of 300 mg of 1-(tert-butoxycarbonyl)pi-
peridin-2-one (1.50 mmol) in 5 mL of THF at –78 °C. After
stirring for 2 h, 1.18 g of N-(5-chloro-2-pyridyl)triflimide
(3.00 mmol) in 5 mL of THF was added. The cold bath was
removed, and the mixture was allowed to warm to 25 °C.
After 1 h the reaction was quenched with 8 mL of a 10%
aqueous solution of sodium hydroxide. The aqueous phase
was extracted with three 5 mL portions of diethyl ether. The
combined ethereal extracts were dried over sodium sulfate,
filtered, and concentrated using rotary evaporation. Purifica-
tion via flash chromatography (1:19 ethyl acetate – hexanes,
containing 1% triethylamine) on silica gel gave 415 mg
(84%) of a clear colourless oil. IR (film) (cm–1): 1726, 1684,
{1-[(4-Methylphenyl)sulfonyl]-1,4,5,6-tetrahydropyridin-
2-yl}(phenyl)methanol (4)
Cloudy colourless oil (yield: 46%). IR (film) (cm–1):
1
3516, 1715, 1455, 1341, 1163. H NMR (400 MHz, CDCl3)
1
δ: 7.61 (d, J = 8.55 Hz, 2H), 7.40–7.10 (m, 7H), 5.84 (d, J =
1.22 Hz, 1H), 5.46 (t, J = 3.66 Hz, 1H), 3.48–3.42 (m, 1H),
3.41–3.35 (m, 1H), 2.40 (s, 3 H), 1.88 (dt, J = 10.68,
1.22 Hz, 2H), 1.39–1.29 (m, 2H). 13C NMR (75 MHz,
CDCl3) δ: 145.2, 143.4, 142.8, 138.1, 131.1, 129.6, 128.9,
128.8, 128.1, 121.5, 75.9, 48.6, 23.5, 22.9, 21.4. LR-MS
(EI) m/z (relative intensity): 343 ([M+ + 1], 8), 205 (11), 189
(19), 188 (100), 170 (22), 108 (23), 107 (25), 105 (18), 91
(36), 86 (37), 82 (27), 79 (38), 77 (35), 65 (13), 58 (15), 55
(29), 51 (12).
1422, 1211, 1141. H NMR (400 MHz, CDCl3) δ: 5.26 (t,
J = 3.97 Hz, 1H), 3.60–3.56 (m, 2H), 2.24 (td, J = 6.71,
3.97 Hz, 2H), 1.77–1.70 (m, 2H), 1.47 (s, H).
Representative procedure for the coupling of lactam-
derived enol triflates with aldehydes: tert-butyl 6-
[hydroxy(phenyl)methyl]-3,4-dihydropyridine-1(2H)-
carboxylate (2)
A round-bottom flask was charged with 111 mg of chro-
mium(II) chloride (0.91 mmol) and 0.4 mg of nickel(II)
chloride (0.003 mmol) and a stirbar. After capping the flask
with a septum, DMF (1 mL) was added, and the thick green
suspension was stirred for 10 min. Benzaldehyde (96 mg,
0.91 mmol) and a solution of 1 (50 mg, 0.15 mmol) in 1 mL
of DMF were added sequentially. The flask containing the
reaction mixture was placed in a sonication bath and
sonicated for 15 h. Diethyl ether (5 mL) and water (2 mL,
containing 1% of triethylamine) was added. The aqueous
phase was extracted with three 3 mL portions of diethyl
ether. The combined organic extracts were dried over so-
dium sulfate, filtered, and concentrated in vacuo. Purifica-
tion via flash chromatography (1:19 ethyl acetate – hexanes,
containing 1% triethylamine) on silica gel gave 29 mg
(66%) of clear colourless oil. IR (film) (cm–1): 3404, 1682,
1-{1-[(4-Methylphenyl)sulfonyl]-1,4,5,6-tetrahydro-
pyridin-2-yl}hexan-1-ol (5)
Clear colourless oil (yield: 42%). IR (film) (cm–1): 3525,
1
1457, 1343, 1161. H NMR (400 MHz, CDCl3) δ: 7.70 (d,
J = 8.24 Hz, 2H), 7.26 (d, J = 7.94 Hz, 2H), 5.60 (t, J =
3.66 Hz, 1H), 4.47 (q, J = 6.10, 1H), 3.48–3.43 (m, 2 H),
3.19 (d, J = 6.10 Hz, 1H), 2.40 (s, 3H), 1.90–1.83 (m, 2H),
1.80–1.60 (m, 2H), 1.42–1.17 (m, 8H), 0.86 (t, J = 6.87 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ: 145.2, 142.9, 138.2,
131.1, 128.8, 119.8, 74.9, 48.7, 36.9, 33.1, 27.1, 24.0, 23.3,
23.0, 21.2, 15.4. LR-MS (EI) m/z (relative intensity): 337
([M+ + 1], 6), 182 (37), 126 (12), 112 (100), 111 (12), 91
(20), 82 (11), 55 (25).
1
1394, 1368, 1256, 1160. H NMR (400 MHz, CDCl3) δ:
7.34–7.15 (m, 5H), 5.85 (bs, 1H), 5.45 (t, J = 3.66 Hz, 1H),
5.35 (d, J = 9.16 Hz, 1H), 3.73 (dt, J = 12.51, 4.27 Hz, 1H),
3.03 (t, J = 10.99 Hz, 1H), 2.19–2.13 (m, 2H), 1.83–1.68
(m, 2H), 1.29 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 155.6,
143.7, 142.9, 129.1, 127.9, 127.2, 119.7, 82.6, 67.2, 46.9,
29.4, 24.5, 24.4. LR-MS (EI) m/z (relative intensity): 289
([M+ + 1], 3), 233 (17), 215 (17), 189 (60), 187 (12), 172
(12), 171 (38), 170 (84), 156 (16), 143 (18), 130 (21), 115
(12), 105 (15), 82 (13), 77 (24), 59 (19), 57 (100), 55 (18).
tert-Butyl 6-[hydroxy(4-methoxyphenyl)methyl]-3,4-
dihydropyridine-1(2H)-carboxylate (6)
Clear colourless oil (yield: 42%). IR (film) (cm–1): 3384,
1695, 1683, 1512, 1395, 1368, 1248, 1160. 1H NMR
(400 MHz, CDCl3) δ: 7.24–7.20 (m, H), 6.83–6.79 (m, 2H),
5.73 (bs, 1H), 5.43 (t, J = 3.66 Hz, 1H), 5.33 (d, J =
8.24 Hz, 1H), 3.77 (s, 3H), 3.70 (dt, J = 12.21, 3.97 Hz,
1H), 3.05 (t, J = 11.60 Hz, 1H), 2.17–2.12 (m, 2H), 1.80–
1.69 (m, 2H), 1.32 (s, 9H). 13C NMR (75 MHz, CDCl3) δ:
159.8, 155.6, 143.3, 136.0, 128.4, 119.2, 114.6, 82.6, 76.9,
56.7, 47.0, 29.5, 24.5, 24.4. LR-MS (EI) m/z (relative inten-
sity): 319 ([M+ + 1], 4), 246 (11), 245 (53), 219 (19), 202
(19), 201 (86), 200 (69), 187 (15), 186 (100), 171 (11), 170
(55), 160 (22), 158 (13), 146 (13), 137 (18), 135 (30), 128
(10), 121 (10), 115 (12), 91 (13), 77 (32), 65 (11), 63 (11),
59 (90), 57 (85), 56 (12), 55 (21), 51 (16).
1-[(4-Methylphenyl)sulfonyl]-1,4,5,6-tetrahydropyridin-2-
yl trifluoromethanesulfonate (3)
To 1-(p-toluenesulfonyl)-piperidin-2-one (200 mg,
0.79 mmol) in THF (6 mL) at –78 °C was added a solution
of potassium bis(trimethylsilyl)amide (189 mg, 0.947 mmol)
in 2 mL of THF. After stirring for 45 min at –78 °C, a solu-
tion of 338 mg of N-phenyltriflimide (0.37 mmol) in 3 mL
© 2004 NRC Canada

Easton and Dake
143
tert-Butyl 6-[2-furyl(hydroxy)methyl]-3,4-dihydropyri-
dine-1(2H)-carboxylate (7)
tert-Butyl 6-{1-hydroxy-3-[(4-methoxybenzyl)oxy]pro-
pyl}-3,4-dihydropyridine-1(2H)-carboxylate (11)
Clear colourless oil (yield: 71%). IR (film) (cm–1): 3420,
Clear colourless oil (yield: 49%). IR (film) (cm–1): 3420,
1681, 1393, 1368, 1161. 1H NMR (400 MHz, CDCl3) δ: 7.30
(s, 1H), 6.28 (dd, J = 3.36, 1.83 Hz, 2H), 5.43 (t, J =
3.66 Hz, 1H), 5.35 (s, 1H), 3.72–3.64 (m, 1H), 3.28–3.19
(m, 1H), 2.15 (td, J = 7.02, 3.66 Hz, 2H), 1.81–1.71 (m,
2H), 1.40 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 156.7,
155.8, 142.8, 141.2, 119.3, 111.5, 107.6, 82.8, 72.4, 46.7,
29.6, 24.5, 24.3. LR-MS (EI) m/z (relative intensity): 279
([M+ + 1], 3), 223 (16), 179 (20), 161 (24), 160 (12), 144
(13), 132 (13), 111 (31), 107 (16), 86 (14), 84 (22), 82 (12),
59 (10), 57 (100), 55 (30).
1
2932, 2860, 1681, 1515, 1393, 1368, 1249, 1161. H NMR
(400 MHz, CDCl3) δ: 7.22 (d, J = 8.55 Hz, 2H), 6.84 (d, J =
8.55 Hz, 2H), 5.41 (t, J = 3.66 Hz, 1H), 5.05 (bs, 1H), 4.41
(dd, J = 18.01, 11.29 Hz, 2H), 4.37–3.31 (m, 1H), 3.77 (s,
3H), 3.59 (s, 1H), 3.56–3.44 (m, 2H), 3.19 (s, 1H), 2.10–
2.05 (m, 2H), 1.92–1.77 (m, 2H), 1.75–1.65 (m, 2H), 1.45
(s, 9H). 13C NMR (75 MHz, CDCl3) δ: 160.6, 155.9, 143.1,
132.0, 130.7, 117.6, 115.2, 82.6, 74.1, 72.8, 68.9, 56.7, 46.9,
36.2, 29.7, 24.6, 24.2. Anal. calcd. for C21H31NO5: C 66.82,
H 8.28, N 3.71; found: C 66.53, H 8.47, N 4.11.
tert-Butyl 6-(1-hydroxy-5-trimethylsilanyl-pent-4-ynyl)-
3,4-dihydropyridine-1(2H)-carboxylate (12)
tert-Butyl 6-(1-hydroxyhexyl)-3,4-dihydropyridine-1(2H)-
carboxylate (8)
Clear colourless oil (yield: 51%). IR (film) (cm–1): 3417,
2961, 2175, 1681, 1392, 1368, 1250, 1162. 1H NMR
(400 MHz, CDCl3) δ: 5.40 (t, J = 3.66 Hz, 1H), 5.19 (bs,
1H), 4.19 (dd, J = 14.65, 8.24 Hz, 1H), 3.76 (dt, J = 11.90,
3.97 Hz, 1H), 3.15 (t, J = 10.68 Hz, 1H), 2.24 (t, J =
7.63 Hz, 2H), 2.10 (m, 2H) 1.86–1.64 (m, 4H), 1.46 (s, 9H),
0.11 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 156.1, 142.6,
118.5, 108.5, 86.0, 82.8, 74.7, 47.0, 35.0, 29.7, 24.6, 24.3,
18.3, 1.6. Anal. calcd. for C18H31NO3Si: C 64.05, H 9.26, N
4.15; found: C 64.45, H 9.40, N 4.45.
Clear colourless oil (yield: 84%). IR (film) (cm–1): 3424,
1
1742, 1683, 1393, 1368, 1256, 1163. H NMR (400 MHz,
CDCl3) δ: 5.38 (t, J = 3.66 Hz, 1H), 5.10 (bs, 1H), 4.05 (dd,
J = 15.26, 7.32 Hz, 1H), 3.75 (dt, J = 11.90, 4.27 Hz, 1H),
3.14 (t, J = 8.85 Hz, 1H), 2.13–2.07 (m, 2H), 1.77–1.69 (m,
2H), 1.46 (s, 9H), 1.35–1.20 (m, 6H), 0.90–0.82 (m, 5H).
13C NMR (75 MHz, CDCl3) δ: 156.1, 143.4, 118.0, 82.6,
75.9, 47.0, 36.1, 33.2, 29.7, 27.3, 24.7, 24.3, 24.0, 15.4. LR-
MS (GC) m/z (relative intensity): 283 ([M+ + 1], 2), 209
(11), 152 (51), 139 (29), 138 (10), 126 (29), 113 (100), 112
(17), 111 (10), 110 (11), 84 (37), 82 (15), 57 (55), 56 (13),
55 (20), 54 (13).
Acknowledgement
We thank the University of British Columbia and the Nat-
ural Sciences and Engineering Research Council of Canada
(NSERC) for the financial support of our research program.
We also thank the Canadian Foundation for Innovation for
enabling specific infrastructure acquisitions.
tert-Butyl 6-(1-hydroxy-2-methylpropyl)-3,4-dihydropyri-
dine-1(2H)-carboxylate (9)
White crystals (yield: 76%), mp 58–60 °C. IR (KBr) (cm–1):
3378, 1670, 1656, 1396, 1367, 1166, 1032. 1H NMR
(400 MHz, CDCl3) δ: 5.38 (t, J = 3.66 Hz, 1H), 5.14 (bs,
1H), 3.83 (d, J = 8.85 Hz, 1H), 3.58 (t, J = 9.16 Hz, 1H),
3.04 (t, J = 9.77 Hz, 1H), 2.13–2.07 (m, 2H), 1.80–1.66 (m,
2H), 1.45 (s, 9H), 0.98 (d, J = 6.71 Hz, 3H), 0.73 (d, J =
6.71 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ: 156.2, 142.7,
119.2, 82.7, 82.6, 47.0, 33.0, 29.7, 24.7, 24.3, 21.2, 20.8.
LR-MS (GC) m/z (relative intensity): 255 ([M+ + 1], 3), 156
(12), 139 (13), 138 (18), 113 (100), 112 (34), 84 (11), 82
(10), 57 (51), 55 (11). Anal. calcd. for C14H25NO3: C 65.85,
H 9.87, N 5.47; found: C 66.25, H 9.98, N 5.28.
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© 2004 NRC Canada