Imino glycals via ruthenium-catalyzed RCM and isomerization

Article abstract of DOI:10.1055/s-0033-1338615

N-Allyl-N-homoallylamines were converted in one step into cyclic enamides via a ruthenium-catalyzed assisted tandem catalytic ring-closing metathesis-isomerization sequence. The sequence relies on the in situ transformation of a metathesis active Ru-carbene into an isomerization active Ru-hydride by addition of hydroxide as a chemical trigger.

Full text of DOI:10.1055/s-0033-1338615

1648▌
PAPER
paper
Imino Glycals via Ruthenium-Catalyzed RCM and Isomerization
Sequential RCM Isomerization
Bernd Schmidt,* Sylvia Hauke, Nino Mühlenberg
Universität Potsdam, Institut für Chemie (Organische Synthesechemie), Karl-Liebknecht-Straße 24-25, 14476 Potsdam-Golm, Germany
Fax +49(331)9775059; E-mail: bernd.schmidt@uni-potsdam.de
Received: 11.02.2014; Accepted after revision: 06.03.2014
annulation),14 and hydroformylation of homoallyl am-
Abstract: N-Allyl-N-homoallylamines were converted in one step
ides.15 Ring-closing olefin metathesis (RCM), although a
into cyclic enamides via a ruthenium-catalyzed assisted tandem cat-
well-established and commonly used method for the syn-
alytic ring-closing metathesis–isomerization sequence. The se-
quence relies on the in situ transformation of a metathesis active
thesis of piperidine and pyrrolidine derivatives via RCM
Ru–carbene into an isomerization active Ru–hydride by addition of of allyl amines or amides,10,16,17 has scarcely been applied
hydroxide as a chemical trigger.
to enamines or enamides. Notable examples have been
published by Rutjes and co-workers,18 who reported the
Key words: heterocycles, isomerization, metathesis, ruthenium,
tandem reaction
synthesis of five- and six-membered cyclic enamides and
by Arisawa et al.,19,20 who described the synthesis of in-
doles. There are two possible reasons for the reluctance of
the synthetic community to use enamide-RCM reactions.
Firstly, the required RCM precursors are less convenient-
ly synthesized than allyl amides, which can be obtained by
simple allylation of deprotonated amides. Secondly, pre-
cursors with electron-rich double bonds are notoriously
difficult metathesis substrates that generally require less
convenient reaction conditions, such as elevated tempera-
tures, more expensive catalysts, or high dilution. A simi-
larly reduced reactivity has also been observed for enol
ethers21–23 and was attributed to the formation of less ac-
tive Fischer-type carbene complexes, resulting from initi-
ation at the electron-rich double bond.24
Glycals, 2,3-unsaturated carbohydrate derivatives with an
enol ether structure,1,2 are useful building blocks for the
synthesis of glycosides and the assembly of oligosaccha-
ride chains.3,4 They have also been extensively used to
synthesize non-carbohydrate natural products.5 The aza
analogues of glycals, sometimes referred to as imino gly-
cals, have attracted less attention, although they are highly
valuable intermediates in the synthesis of target molecules
such as indolizidine alkaloids,6 aza-C-nucleosides,7 piper-
idine alkaloids,8–10 and aza sugars (Scheme 1).11
H
N
HO
N
To circumvent these obstacles in the metathesis-based
synthesis of cyclic enol ethers, the group of Snapper25 and
one of us26,27 have independently developed an assisted
tandem catalytic RCM–isomerization sequence. Assisted
tandem catalytic sequences28 rely on the use of just one
precatalyst (a Ru–carbene in the case of a metathesis reac-
tion) which is converted into a catalyst for a different
transformation (e.g., a Ru–hydride to mediate an isomeri-
zation). This organometallic transformation is triggered
by the addition of an appropriate reagent after completion
of the first transformation of the sequence. Apart from one
example in Snapper’s original contribution,25 a cyclic en-
amide has so far only once, and inadvertently, been syn-
thesized through RCM–isomerization (Scheme 2).29
H
OH
OH
aza sugar
analogues
indolizidine
alkaloid 167B
R1
N
R2
R3
O
imino glycals
H
N
NH2
H
N
HO
HO
HO
HO
OH
piperidine alkaloid
(+)-prosopinine
aza-C-nucleosides
Scheme 1 Selected synthetic applications of imino glycals
Boc
N
Boc
N
Boc
N
cat. A or B
(5 mol%)
+
Methods for the synthesis of imino glycals include the re-
duction of lactams and subsequent elimination,12 electro-
chemical oxidation of piperidines, followed by
elimination,13 addition of nucleophiles to pyridinium salts
and subsequent partial reduction,6 nucleophilic ring open-
ing of aziridines followed by cyclization (formal [3+3]-
HO
HO
HO
CH2Cl2, 20 °C
1
2
3
PCy3
MesN
Cl
NMes
Cl
2
3
cat.
Cl
Ru
A
60%
85%
40%
15%
Ru
Ph
Cl
Ph
PCy3
B
PCy3
A
B
SYNTHESIS 2014, 46, 1648–1658
Advanced online publication: 28.03.2014
Scheme 2 Inadvertent and uncontrolled RCM–isomerization29
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338615; Art ID: SS-2014-T0099-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Sequential RCM Isomerization
1649
Park and co-workers reported that allylamide 1 reacts un- be attributed to either a Ru–hydride impurity or the specif-
der metathesis conditions to give a 3:2 mixture of the ex- ic structure of the metathesis substrate. For these reasons
pected and desired product 2 and the undesired enamide 3 we thought that a general, reliable, reproducible, and pro-
if the first-generation catalyst A30 is used. The ratio is sig- jectable RCM–isomerization sequence should rely on the
nificantly improved with the second-generation catalyst use of a suitable additive to trigger the required conver-
B.31 Undesired competing or subsequent isomerization re- sion of the metathesis into an active isomerization cata-
actions may be caused by contaminations of the precata- lyst. To identify suitable conditions, we chose the N-Boc-
lyst with Ru–hydrides (originating from washing the allyl amine 4a as a test substrate (Table 1).
crude precatalyst with alcohols32–34) or by uncontrolled
With first-generation catalyst A, the RCM step was com-
catalyst decomposition during the metathesis reaction.
plete within two hours at 80 °C. The crude reaction mix-
For first-generation catalyst A, Ru–hydrides have not
ture contained only the expected RCM product 5a,
been identified as products from thermal decomposition
whereas the isomerized product 6a was not observed by
reactions.35 This makes it more likely that the large
1H NMR spectroscopy. In the next experiment we
amount of isomerization product 3 observed by Park and
checked if triggering the isomerization step requires an
co-workers is either caused by a Ru–hydride impurity
additive, or if the metathesis catalyst, contrary to previous
present in the precatalyst, or can be attributed to the spe-
literature reports for first-generation catalysts,35 can be
cific structure of the metathesis substrate. In contrast,
thermally converted into an isomerization catalyst. To this
second-generation catalyst B is known to decompose ther-
end, the reaction temperature was increased to 110 °C for
mally through a bimolecular pathway to a Ru–hydride.36
16 hours after completion of the RCM reaction (Table 1,
However, it has recently been questioned that this partic-
entry 1). The 1H NMR spectrum of the crude reaction mix-
ular decomposition product is catalytically competent in
ture showed that no cyclic enamide 6a was formed, which
isomerization reactions,37 which suggests that the forma-
strongly underlines the necessity to use a chemical trigger
tion of isomerized product 3 with precatalyst B may also
Table 1 Optimization of RCM–Isomerization Conditions
Boc
Boc
N
cat. (n mol%), toluene (0.1 M), 80 °C, 2 h;
then additive, 110 °C, 16 h
Ph
N
Ph
4a
6a
Boc
Ph
N
5a
Entry
Catalyst
Catalyst loading (mol%)
Additive (equiv)
Yield(%) of 6a
a
1
2
A
A
A
A
A
A
A
A
B
B
B
B
B
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
2.5
2.5
2.5
2.5
2.5
none
–
a
EtOCH=CH2 (5)
NaH (0.5)
–
a
3
–
a
4
NaBH4 (0.5)
Et3SiH (1.0)
–
5
69b
31c
65
6
PMHS (0.2)
7
NaOH (1.5), i-PrOH (25%)
NaOH (1.5)
8
51
9
none
64d
57
10
11
12
13
Et3SiH (1.0)
PMHS (0.2)
17
NaOH (1.5), i-PrOH (25%)
NaOH (1.5)
81
84
a Not detected, only RCM product 5a was observed.
b RCM product 5a (17%) was also isolated.
c Major amounts of 5a were detected by NMR spectroscopy, but not isolated.
d RCM product 5a (35%) was also isolated.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1648–1658

1650
B. Schmidt et al.
PAPER
for the projected RCM–isomerization sequence. First, we tions (toluene, 80 °C, 2 h) in the presence of 2.5 mol% of
tested three different additives that had previously proven B. Conversion to the RCM product 5a, which could be
useful in triggering the isomerization step. Ethyl vinyl isolated in 87% yield, was quantitative and isomerization
ether (entry 2) is often used to terminate metathesis reac- was not observed. Next, this experiment was repeated, but
tions, because it reacts with the alkylidene species to an upon completion of the metathesis reaction the tempera-
inactive Fischer-type carbene complex. Upon heating, ture was raised to 110 °C for 16 hours (entry 9). These
this complex is converted into a Ru–hydride24 that is ca- conditions led to the isolation of 6a and 5a in a ratio of ca.
pable of isomerizing allyl ethers to enol ethers.38 Sodium 2:1. While this experiment reveals that either B, its methy-
hydride and sodium borohydride (entries 3 and 4) have lidene analogue (the propagating species of the metathesis
been discovered by one of us as suitable reagents for con- reaction), or a degradation product show some isomeriza-
verting Ru–alkylidenes into isomerization catalysts with a tion activity, it also clearly demonstrates that triggering
Ru–hydride structure.26 Unfortunately, all these additives, the isomerization exclusively by heating is insufficient for
which were found to be highly successful for the analo- satisfactory rates of conversion. Therefore, B was tested
gous oxacycles, do not induce any isomerization of 4a, as in combination with the additives that were previously
indicated by 1H NMR spectroscopy of the crude reaction identified as suitable chemical triggers for the first-gener-
mixtures. The first successful RCM–isomerization was ation catalyst. With both silanes, triethylsilane (entry 10)
accomplished using triethylsilane,27 which had also been and polymethylhydroxysilane (entry 11) the yield of 6a
previously established as an isomerization inducing addi- was significantly lower than that for thermally induced
tive by us (entry 5). The cyclic enamide 6a was isolated in isomerization. In particular polymethylhydrosiloxane
69% yield, along with the RCM product 5a (17%). The might even be considered as an isomerization-preventing
less expensive polymethylhydrosiloxane39 was signifi- additive for second-generation catalysts, although its role
cantly less effective and furnished the isomerization prod- is currently completely unclear. In contrast to the silanes,
uct 6a only in 31% yield, along with major amounts of 5a both sodium hydroxide (entry 13) and sodium hydroxide
(entry 6). Silanes (up to 5 equiv) have previously been in combination with propan-2-ol as a co-solvent (entry 12)
used as hydrogen substitutes in tandem RCM–hydrogena- were highly successful additives, leading to a quantitative
1
tion sequences,40 which prompted us to check the H isomerization; isolated yields of 6a were typically be-
NMR spectra for signals arising from the corresponding tween 80% and 85%. For reasons of experimental sim-
piperidine. However, no hydrogenation product could be plicity, solid sodium hydroxide was used in the following
detected in the crude reaction mixture, which can proba- experiments as a single isomerization-inducing additive.
bly be explained by the lower amount of silane used in our
experiments. Another successful reagent combination for
To evaluate the scope of the method, we synthesized a set
of precursors 4a–g following a sequence previously re-
inducing isomerization reactions is propan-2-ol as a co-
ported by Aubé and co-workers.45 The corresponding al-
solvent and sodium hydroxide as a base (entry 7).41 We
dehydes 7 were condensed with allylamine (8), followed
by addition of allylmagnesium bromide to give the inter-
mediate N-allyl-N-homoallylamines 9, which were even-
tually protected as Boc-amides 4a–g. Subjecting these
have previously discovered that under these conditions a
Ru–hydride is formed,27 and a thorough investigation of
the pathways leading from first-generation catalyst A to a
six-coordinate Ru–hydride complex upon treatment with
precursors to the optimized conditions (from Table 1, en-
alkoxides has recently been published by Fogg and co-
try 13) furnished the cyclic enamides 6a–g in most cases
in good yields (Table 2). An exception is the cyclohexyli-
dene-protected derivative 6e, which was obtained in a
moderate yield of 38%. We have no indication that the
workers.42 Application of the propan-2-ol/sodium hydrox-
ide combination to the RCM–isomerization of the test
substrate 4a furnished the isomerized product 6a in a yield
comparable to that obtained with triethylsilane (see entry
isomerization is incomplete or less selective in this partic-
5 for comparison). Interestingly, with sodium hydroxide
ular case, suggesting that a considerable amount of prod-
as a single additive the isomerization reaction still
uct is lost during chromatographic purification.
worked, but the isolated yield of 6a was significantly low-
As an illustrative application of this RCM–isomerization
er (entry 8). At this point we thought that no further im-
sequence we investigated the synthesis of the imino gly-
provement could be achieved by testing other additives
cals 6h,i (Scheme 3). These imino glycals are fully pro-
and therefore turned our attention to the precatalyst. The
second-generation catalyst B has occasionally been re-
tected aza analogues of L-rhodinal,46 the glycal of the
2,3,6-tridesoxy sugar47 L-rhodinose, and are potentially
ported to promote isomerization reactions, in particular at
useful building blocks for the synthesis of azasugars or pi-
higher catalyst loadings and elevated temperatures, even
peridine alkaloids, as outlined in the introduction.
in the absence of an additive.43 For example, Fustero et al.
discovered that geminally difluorinated unsaturated ε-
caprolactams can be synthesized via RCM. Remarkably,
the isomerization is completely suppressed with the first-
generation catalyst A, but occurs quantitatively with
second-generation catalyst B.44 We started this part of the
optimization study with a control experiment: the test sub-
strate 4a was subjected to the standard metathesis condi-
The synthesis starts from L-alanine (10), which was con-
verted into the N-Boc-protected 11a and N-Cbz-protected
L-alanine methyl esters 11b, respectively.48 Their reduc-
tion with diisobutylaluminum hydride at low temperature
furnished the respective aldehydes 12a and 12b,48 which
were then treated with vinylmagnesium chloride to give
the allyl alcohols 13a and 13b. This reaction had previ-
Synthesis 2014, 46, 1648–1658
© Georg Thieme Verlag Stuttgart · New York

PAPER
Sequential RCM Isomerization
1651
ously been investigated by Jurczak and co-workers,49 who chiral aldehydes50 can be improved by using less strongly
reported diastereomeric ratios of ca. 3:2 for 12a and ca. coordinating solvents, such as dichloromethane.51
3:1 for 12b, using tetrahydrofuran as a solvent at 0 °C. We
This led indeed to a diastereomeric ratio of 4:1 for both
repeated the Grignard reaction for the N-Boc derivative
13a and 13b, which could be isolated in comparable
12a using Jurczak’s conditions and obtained 13a in an
yields. In the following step the secondary alcohol was
protected as a MOM ether 14a or as a BOM ether 14b, to
allow for selective N-allylation after deprotonation of the
only marginally higher diastereomeric ratio. It had previ-
ously been reported that the diastereoselectivity of chela-
tion-controlled addition reactions of organometallics to α-
Table 2 Synthesis of Precursors 4a–g and Yields of RCM–Isomerization Products 6a–g
H2N
(1.2 equiv)
1)
Boc2O (1.6 equiv)
Et3N (1.3 equiv)
CH2Cl2, 20 °C, 16 h
B (2.5 mol%), toluene (0.1 M)
80 °C, 2 h; then add NaOH
(s, 1.5 equiv), 110 °C, 16 h
H
Boc
N
Boc
N
8
R
N
R
R
R
H
MgSO4, CH2Cl2, 20 °C, 16 h
O
BrMg
(2.0 equiv)
2)
7
9
4
6
CH2Cl2, 20 °C, 16 h
Entry
1
Aldehyde 7
Amine 9
Yield (%) N-Boc amide 4
Yield (%) Cyclic enamide 6
Yield (%)
H
Boc
N
N
Boc
N
H
40
85
84
O
7a
6a
9a
4a
Br
Br
Br
Br
H
Boc
N
Boc
N
N
H
2
3
4
56
90
39
69
80
64
83
O
7b
6b
9b
MeO
4b
MeO
MeO
MeO
Boc
H
N
Boc
N
N
H
70
66
O
7c
6c
9c
BnO
4c
BnO
BnO
BnO
Boc
H
N
Boc
N
N
H
O
7d
6d
9d
4d
O
O
O
H
O
Boc
O
O
N
Boc
N
O
O
N
H
5
32
92
39
O
7e
7f
6e
9e
4e
H
N
Boc
Boc
N
H
N
O
6
7
10
47
95
54
77
83
6f
9f
4f
H
Boc
N
N
Boc
TBSO
TBSO
N
H
TBSO
TBSO
O
7g
6g
4g
9g
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1648–1658

1652
B. Schmidt et al.
PAPER
at r.t., the mixture was filtered, and the filter cake washed several
times with t-BuOMe. Evaporation of the solvent gave the crude im-
ine, which was dissolved in anhyd CH2Cl2. Then, ca. 0.4 M allyl-
magnesium bromide in Et2O (2.0 equiv) was added dropwise and
the solution was stirred for 16 h at r.t. The reaction was quenched
by the addition of sat. aq NH4Cl soln, the organic layer was separat-
ed and the aqueous layer was extracted t-BuOMe (3 ×). The com-
bined organic extracts were dried (MgSO4), filtered, and
evaporated. The residue was purified by column chromatography to
yield the amine 9.
1) SOCl2 (2.2 equiv)
MeOH, 40 °C, 3.5 h
DIBAL-H
NH2
NHPG1
OMe
(2.2 equiv)
2) Boc2O (1.6 equiv)
Et3N, CH2Cl2, 20 °C, 3 h
(for 11a) or
CbzCl (1.1 equiv)
K2CO3, H2O–EtOAc
(1:1), 20 °C, 2 h (for 11b)
CH2Cl2
–78 °C, 1 h
O
OH
O
10
11a (PG1 = Boc, 98%)
11b (PG2 = Cbz, 90%)
MgCl
(2.3 equiv)
NHPG1
H
MOMBr (1.3 equiv) or
BOMCl (2.6 equiv)
NHPG1
CH2Cl2
0 °C, 2 h
i-Pr2NEt, DMAP
(0.2 equiv), CH2Cl2
40 °C, 16 h
N-Allyl-1-phenylbut-3-en-1-amine (9a)
Following the general procedure, 7a (3.00 g, 28.3 mmol) was con-
verted into 9a (2.10 g, 11.2 mmol, 40%); colorless liquid.
O
HO
12a (96%)
12b (91%)
13a (74%); dr = 4:1
13b (70%); dr = 4:1
IR (ATR): 3075 (w), 2911 (w), 1640 (w), 1454 (m), 933 (s), 914 (s),
699 cm–1 (s).
PG1
N
NaH (3.0 equiv)
allyl bromide (2.0 equiv)
NHPG1
1H NMR (300 MHz, CDCl3): δ = 7.35–7.20 (m, 5 H), 5.86 (dddd,
J = 17.0, 10.2, 6.6, 5.5 Hz, 1 H), 5.73 (dddd, J = 16.9, 10.1, 7.5, 6.5
Hz, 1 H), 5.16–5.01 (m, 4 H), 3.70 (t, J = 7.2 Hz, 1 H), 3.13 (dddd,
J = 14.1, 5.4, 1.5, 1.5 Hz, 1 H), 3.02 (dddd, J = 14.1, 6.6, 1.2, 1.2
Hz, 1 H), 2.47–2.36 (m, 2 H), 1.62 (br s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 143.7 (0), 136.9 (1), 135.4 (1),
128.3 (1), 127.2 (1), 127.0 (1), 117.4 (2), 115.6 (2), 61.8 (1), 50.0
(2), 42.9 (2).
TBAI (0.1 equiv)
THF, 65 °C, 3 h
PG2O
PG2O
14a (PG1 = Boc,
PG2 = MOM; 79%)
14b (PG2 = Cbz,
PG2 = BOM; 74%)
4h (PG1 = Boc,
PG2 = MOM; 55%)
4i (PG2 = Cbz,
PG2 = BOM; 90%)
PG1
N
B (2.5 mol%), toluene (0.1 M),
80 °C, 2 h; then add NaOH
(s; 1.5 equiv), 110 °C, 16 h
MS (EI): m/z (%) = 146 (40), 91 (21), 71 (22), 57 (38), 41 (100).
HRMS (ESI): m/z [M + H]+ calcd for C13H18N: 188.1439; found:
188.1432.
PG2O
6h (PG1 = Boc, PG2 = MOM; 91%)
6i (PG2 = Cbz, PG2 = BOM; 79%)
N-Allyl-1-(4-bromphenyl)but-3-en-1-amine (9b)
Following the general procedure, 7b (3.00 g, 16.2 mmol) was con-
verted into 9b (2.41 g, 9.1 mmol, 56%); colorless liquid.
Scheme 3 Application to the synthesis of 2,3,6-tridesoxy imino gly-
cals 6h,i
IR (ATR): 3076 (w), 1640 (w), 1486 (m), 1010 (s), 915 (s), 820
cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.44 (dm, J = 8.4 Hz, 2 H), 7.19
(dm, J = 8.4 Hz, 2 H), 5.83 (ddt, J = 17.0, 10.2, 5.4 Hz, 1 H), 5.69
(ddt, J = 16.9, 10.1, 6.5 Hz, 1 H), 5.14–5.09 (m, 2 H), 5.09–5.02 (m,
2 H), 3.67 (t, J = 7.0 Hz, 1 H), 3.10 (dddd, J = 14.2, 5.4, 1.5, 1.5 Hz,
1 H), 2.98 (dddd, J = 14.1, 6.7, 1.1, 1.1 Hz, 1 H), 2.41–2.28 (m, 2
H), 1.66 (br s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 142.8 (0), 136.7 (1), 134.9 (1),
131.4 (1), 129.0 (1), 120.6 (0), 117.8 (2), 115.8 (2), 61.2 (1), 49.9
(2), 42.8 (2).
amide with sodium hydride. The resulting precursors 4h,i
were then subjected to the optimized RCM–isomerization
conditions to give the desoxy imino glycals 6h,i.
In summary, we have developed an assisted tandem cata-
lytic RCM–isomerization reaction for the synthesis of cy-
clic enamides. The sequence requires only one catalyst,
which mediates two independent transition-metal-cata-
lyzed transformations in a defined order. The method has
been applied to the synthesis of aza analogues of 2,3,6-
tridesoxy glycals. Application to the synthesis of target
molecules, in particular alkaloids, is currently under in-
vestigation in our laboratory.
HRMS (ESI): m/z [M + H]+ calcd for C13H17NBr: 266.0544; found:
266.0542.
Anal. Calcd for C13H16NBr (266.18): C, 58.7; H, 6.1; N, 5.3. Found:
C, 58.3; H, 6.4; N, 5.8.
N-Allyl-1-(4-methoxyphenyl)but-3-en-1-amine (9c)
Following the general procedure, 7c (1.00 g, 7.30 mmol) was con-
verted into 9c (1.44 g, 6.60 mmol, 90%); colorless liquid.
All experiments were conducted in dry reaction vessels under an at-
mosphere of dry N2. Solvents were purified using a commercial sol-
vent purification system. H NMR spectra were obtained at 300
1
IR (ATR): 3073 (w), 1609 (w), 1510 (s), 1459 (m), 1243 (s), 1034
(s), 914 (s), 830 cm–1 (s).
MHz or at 500 MHz in CDCl3 with CHCl3 (δ = 7.26) as an internal
standard. 13C NMR spectra were recorded at 75 MHz or at 125 MHz
in CDCl3 with CDCl3 (δ = 77.0) as an internal standard. The number
of coupled protons was analyzed by DEPT or APT experiments and
is denoted by a number in parentheses following the chemical shift
value. In many cases signals are broad or split up due to hindered
rotation of the Boc group or quadrupole broadening. FT-IR spectra
were recorded on an ATR-crystal. Mass spectra were obtained us-
ing EI or ESI/TOF. N-Protected L-alanine methyl esters 11a,b have
been described previously.48
1H NMR (300 MHz, CDCl3): δ = 7.22 (dm, J = 8.6 Hz, 2 H), 6.87
(dm, J = 8.7 Hz, 2 H), 5.85 (ddt, J = 17.0, 10.2, 5.5 Hz, 1 H), 5.71
(ddt, J = 17.1, 10.1, 7.1 Hz, 1 H), 5.15–5.09 (m, 1 H), 5.09–4.98 (m,
3 H), 3.80 (s, 3 H), 3.65 (t, J = 6.9 Hz, 1 H), 3.11 (dddd, J = 14.1,
5.4, 1.6, 1.5 Hz, 1 H), 3.00 (dddd, J = 14.1, 6.6, 1.2, 1.2 Hz, 1 H),
2.40 (ddm, J = 7.0, 6.5 Hz, 2 H), 1.66 (br s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 158.7 (0), 137.0 (1), 135.7 (0),
135.5 (1), 128.2 (1), 117.3 (2), 115.6 (2), 113.7 (1), 61.1 (1), 55.2
(3), 49.9 (2), 42.9 (2).
N-Allyl N-Homoallyl Amines 9; General Procedure
MS (EI): m/z (%) = 176 (100), 161 (48), 134 (36), 121 (27), 91 (16),
57 (18), 41 (46).
To a solution of the corresponding aldehyde 7 in CH2Cl2 (1.5
mL/mmol) was added allylamine (8, 1.2 equiv) and MgSO4 (1.00 g
per 10.0 mmol of aldehyde 7). The suspension was stirred for 16 h
Synthesis 2014, 46, 1648–1658
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Sequential RCM Isomerization
1653
HRMS (ESI): m/z [M + H]+ calcd for C14H20NO: 218.1545; found:
218.1533.
(2S,3R)-N-Allyl-2-(tert-butyldimethylsilyloxy)hex-5-en-3-amine
(9g)
Following the general procedure, 7g (1.80 g, 9.6 mmol) was con-
verted into 9g (1.20 g, 4.5 mmol, 47%, single diastereomer); color-
less liquid.
[α]D26 –2.8 (c 0.17, CH2Cl2).
N-Allyl-1-(4-benzyloxyphenyl)but-3-en-1-amine (9d)
Following the general procedure, 7d (2.50 g, 11.8 mmol) was con-
verted into 9d (1.35 g, 4.6 mmol, 39%); colorless liquid.
IR (ATR): 3069 (w), 1608 (m), 1509 (s), 1235 (s), 916 (s), 736
cm–1 (s).
IR (ATR): 3077 (w), 2931 (m), 1641 (w), 1466 (m), 1253 (m), 1094
(m), 913 (m), 832 (s), 773 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.52–7.30 (m, 5 H), 7.26 (d,
J = 8.7 Hz, 2 H), 6.97 (d, J = 8.6 Hz, 2 H), 5.89 (ddt, J = 16.8, 10.3,
5.7 Hz, 1 H), 5.74 (ddt, J = 17.1, 10.0, 7.1 Hz, 1 H), 5.19–5.02 (m,
4 H), 5.07 (s, 2 H), 3.68 (t, J = 6.8 Hz, 1 H), 3.15 (ddm, J = 14.1, 5.4
Hz, 1 H), 3.04 (dd, J = 14.1, 6.6 Hz, 1 H), 2.43 (dd, J = 6.9, 6.7 Hz,
2 H), 1.69 (br s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 158.0 (0), 137.2 (0), 137.0 (1),
136.0 (0), 135.5 (1), 128.5 (1), 128.3 (1), 127.9 (1), 127.5 (1), 117.3
(2), 115.6 (2), 114.7 (1), 70.1 (2), 61.1 (1), 49.9 (2), 42.9 (2).
1H NMR (300 MHz, CDCl3): δ = 5.95–5.74 (m, 2 H), 5.16 (dddd,
J = 17.2, 1.7, 1.6, 1.6 Hz, 1 H), 5.11–4.98 (m, 3 H), 3.83 (qd,
J = 6.2, 5.3 Hz, 1 H), 3.29 (dddd, J = 14.0, 5.9, 1.4, 1.3 Hz, 1 H),
3.20 (dddd, J = 14.0, 6.1, 1.4, 1.3 Hz, 1 H), 2.45 (ddd, J = 7.1, 7.1,
4.9 Hz, 1 H), 2.34 (m, 1 H), 2.03 (m, 1 H), 1.44 (br s, 1 H), 1.12 (d,
J = 6.2 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 137.6 (1), 136.7 (1), 116.4 (2),
115.4 (2), 69.6 (1), 62.5 (1), 50.6 (2), 34.4 (2), 25.9 (3), 19.3 (3),
18.0 (0), –4.2 (3), –4.8 (3).
MS (EI): m/z (%) = 253 (17), 254 (100), 161 (6), 91 (62), 41 (6).
HRMS (ESI) m/z [M + H]+ calcd for C20H24NO: 294.1858; found:
294.1832.
MS (EI): m/z (%) = 110 (100), 73 (9), 41 (13).
HRMS (ESI): m/z [M + H]+ calcd for C15H32NOSi: 270.2253;
found: 270.2270.
Anal. Calcd for C20H23NO (293.40): C, 81.9; H, 7.9; N, 4.8. Found:
C, 81.3; H, 7.9; N, 4.6.
Anal. Calcd for C15H31NOSi (269.50): C, 66.9; H, 11.6; N, 5.2.
Found: C, 66.8; H, 11.7; N, 5.3.
N-Allyl-1-(1,4-dioxaspiro[4.5]decan-2-yl)but-3-en-1-amine (9e)
Following the general procedure, 7e (4.00 g, 23.5 mmol) was con-
verted into 9e (1.90 g, 7.6 mmol, 32%) in a diastereomeric ratio of
3:1; colorless liquid. Analytical data of the major diastereomer were
obtained from the mixture.
Synthesis of N-Boc-Protected Amines 4; General Procedure
The corresponding secondary amine 9 (1.0 equiv) was dissolved in
anhyd and degassed CH2Cl2 (6.0 mL/mmol). Et3N (1.3 equiv) and
Boc2O (1.6 equiv) were added, and the solution was stirred at r.t. for
16 h. The reaction was quenched by the addition of sat. aq NH4Cl,
the organic layer was separated, and the aqueous layer was extract-
ed with t-BuOMe. The combined organic extracts were dried
(MgSO4), filtered, and evaporated. The residue was purified by
chromatography (silica gel) to furnish the corresponding Boc-
protected derivatives 4.
IR (ATR): 3075 (w), 2933 (s), 1640 (m), 1162 (m), 1100 (s), 913
cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 5.94–5.71 (m, 2 H), 5.16 (ddd,
J = 17.2, 3.3, 1.6 Hz, 1 H), 5.13–5.02 (m, 3 H), 4.05 (td, J = 6.8, 6.7
Hz, 1 H), 3.98 (td, J = 6.4, 6.3 Hz, 1 H), 3.68 (dd, J = 7.6, 7.1 Hz, 1
H), 3.33 (dddd, J = 14.1, 5.9, 1.4, 1.4 Hz, 1 H), 3.28 (dddd, J = 14.0,
6.2, 1.4, 1.3 Hz, 1 H), 2.68 (m, 1 H), 2.25 (m, 1 H), 2.07 (m, 1 H),
1.83 (br s, 1 H), 1.69–1.48 (m, 8 H), 1.43–1.31 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 137.1 (1), 134.9 (1), 117.5 (2),
115.7 (2), 109.4 (0), 77.8 (1), 66.4 (2), 58.7 (1), 50.3 (2), 36.3 (2),
35.2 (2), 34.9 (2), 25.2 (2), 24.0 (2), 23.8 (2).
MS (EI): m/z (%) = 251 (1, [M]+), 210 (10), 112 (18), 110 (100), 41
(53).
HRMS (EI): m/z [M]+ calcd for C15H25NO2: 251.1885; found:
251.1897.
tert-Butyl Allyl(1-phenylbut-3-enyl)carbamate (4a)
Following the general procedure, 9a (1.00 g, 5.3 mmol) was con-
verted into 4a (1.30 g, 4.5 mmol, 85%); colorless liquid.
IR (ATR): 3075 (w), 2976 (w), 1687 (s), 1395 (s), 1169 (s), 1141
(s), 913 (s), 699 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.36–7.25 (m, 5 H), 5.82 (ddt,
J = 17.0, 10.2, 6.8 Hz, 1 H), 5.62 (br m, 1 H), 5.36 (br m, 1 H), 5.13
(ddt, J = 17.1, 1.7, 1.5 Hz, 1 H), 5.06 (dm, J = 10.2 Hz, 1 H), 5.01–
4.85 (m, 2 H), 3.82–3.41 (m, 2 H), 2.81–2.65 (m, 2 H), 1.46 (br s, 9
H).
13C NMR (75 MHz, CDCl3): δ = 155.7 (0), 140.4 (0), 135.8 (1),
135.2 (1), 128.2 (1), 127.9 (1), 127.3 (1), 117.1 (2), 115.6 (2), 79.7
(0), 58.0 (1), 46.5 (2), 35.6 (2), 28.4 (3).
N-Allyl-6-methylhept-1-en-4-amine (9f)
Following the general procedure, 7f (3.00 g, 34.8 mmol) was con-
verted into 9f (0.60 g, 3.6 mmol, 10%); colorless liquid.
MS (EI): m/z (%) = 246 (3), 190 (21), 146 (36), 57 (100), 41 (41).
HRMS (ESI): m/z [M + H]+ calcd for C18H26NO2: 288.1964; found:
IR (ATR): 3076 (m), 2955 (s), 1641 (m), 1463 (s), 994 (s), 912
cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 5.86 (ddt, J = 16.9, 10.2, 6.1 Hz,
1 H), 5.76 (ddt, J = 16.8, 9.5, 7.1 Hz, 1 H), 5.13 (dtd, J = 17.2, 3.3,
1.6 Hz, 1 H), 5.09–5.01 (m, 3 H), 3.21 (ddd, J = 6.0, 2.6, 1.3 Hz, 2
H), 2.63 (tt, J = 6.5, 6.2 Hz, 1 H), 2.27–2.03 (m, 2 H), 1.66 (sept.,
J = 6.6 Hz, 1 H), 1.40 (br s, 1 H), 1.34–1.13 (m, 2 H), 0.87 (d,
J = 6.6 Hz, 3 H), 0.87 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 137.2 (1), 135.5 (1), 117.1 (2),
115.6 (2), 54.0 (1), 49.6 (2), 43.7 (2), 38.5 (2), 24.8 (1), 22.9 (3),
22.8 (3).
288.1997.
Anal. Calcd for C18H25NO2 (187.28): C, 75.2; H, 8.8; N, 4.9. Found:
C, 75.2; H, 8.8; N, 4.8.
tert-Butyl Allyl[1-(4-bromophenyl)but-3-enyl]carbamate (4b)
Following the general procedure, 9b (2.32 g, 8.7 mmol) was con-
verted into 4b (2.21 g, 6.0 mmol, 69%); colorless liquid.
IR (ATR): 2975 (w), 1686 (s), 1395 (s), 1169 (s), 1142 (s), 915
cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.43 (dm, J = 8.5 Hz, 2 H), 7.19
(dm, J = 8.3 Hz, 2 H), 5.77 (ddt, J = 17.0, 10.2, 6.8 Hz, 1 H), 5.58
(br m, 1 H), 5.33 (br m, 1 H), 5.18–4.82 (m, 4 H), 3.83–3.35 (m, 2
H), 2.68 (dm, J = 6.8 Hz, 2 H), 1.44 (br s, 9 H).
MS (EI): m/z (%) = 163 (7), 126 (59), 105 (32), 91 (100), 77 (23),
55 (40), 41 (82).
HRMS (ESI): m/z [M + H]+ calcd for C11H22N: 168.1752; found:
168.1768.
13C NMR (75 MHz, CDCl3): δ = 155.6, 139.5, 135.5, 134.7, 131.4,
129.6, 121.2, 117.4, 115.9, 79.9, 57.5, 46.6, 35.6, 28.4.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1648–1658

1654
B. Schmidt et al.
PAPER
MS (EI): m/z (%) = 326 (14), 324 (15), 270 (55), 268 (61), 226 (45),
224 (52), 129 (19), 57 (100).
HRMS (ESI): m/z [M + H]+ calcd for C20H34NO4: 352.2488; found:
352.2482.
HRMS (ESI): m/z [M + H]+ calcd for C18H25NO2Br: 366.1069;
found: 366.1086.
Anal. Calcd for C20H33NO4 (351.48): C, 68.3; H, 9.5; N, 4.0. Found:
C, 68.5; H, 9.8; N, 4.1.
Anal. Calcd for C18H24NO2Br (366.29): C, 59.0; H, 6.6; N, 3.8.
Found: C, 58.7; H, 7.0; N, 4.3.
tert-Butyl Allyl(6-methylhept-1-en-4-yl)carbamate (4f)
Following the general procedure, 9f (0.46 g, 2.7 mmol) was con-
verted into 4f (0.70 g, 2.6 mmol, 95%); colorless liquid.
tert-Butyl Allyl[1-(4-methoxyphenyl)but-3-enyl]carbamate (4c)
Following the general procedure, 9c (1.33 g, 6.1 mmol) was con-
verted into 4c (1.37 g, 4.3 mmol, 70%); colorless liquid.
IR (ATR): 3078 (w), 2925 (m), 1691 (s), 1364 (s), 1246 (s), 1157
(s), 914 cm–1 (s).
IR (ATR): 2975 (w), 1684 (s), 1513 (s), 1395 (s), 1246 (s), 1171 (s),
1141 (s), 913 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 5.97–5.60 (m, 2 H), 5.19–4.91 (m,
4 H), 4.13 (br m, 1 H), 3.81–3.49 (m, 2 H), 2.32–2.03 (m, 2 H),
1.60–1.49 (m, 2 H), 1.44 (br s, 9 H), 1.15 (m, 1 H), 0.90 (d, J = 6.5
Hz, 3 H), 0.86 (d, J = 6.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 155.8 (0), 136.5 (1), 136.1 (1),
135.8 (1), 135.6 (1), 116.6 (2), 116.5 (2), 115.6 (2), 115.4 (2), 79.1
(0), 54.4 (1), 53.2 (1), 45.4 (2), 42.3 (2), 41.8 (2), 38.6 (2), 38.4 (2),
28.4 (3), 23.2 (1).
1H NMR (300 MHz, CDCl3): δ = 7.22 (d, J = 8.6 Hz, 2 H), 6.85
(dm, J = 8.8 Hz, 2 H), 5.79 (ddt, J = 17.1, 10.2, 6.8 Hz, 1 H), 5.59
(br m, 1 H), 5.33 (br m, 1 H), 5.11 (ddt, J = 17.2, 1.7, 1.4 Hz, 1 H),
5.04 (dm, J = 10.2 Hz, 1 H), 5.00–4.86 (m, 2 H), 3.79 (s, 3 H), 3.71–
3.39 (m, 2 H), 2.68 (dm, J = 7.5 Hz, 2 H), 1.46 (br s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 158.8, 155.7, 135.8, 135.3, 132.3,
129.1, 117.0, 115.5, 113.6, 79.6, 57.4, 55.2, 46.1, 35.8, 28.4.
MS (EI): m/z (%) = 226 (7), 170 (38), 126 (45), 57 (100), 41 (26).
MS (EI): m/z (%) = 276 (20), 220 (100), 176 (52), 161 (17), 134
HRMS (ESI): m/z [M + H]+ calcd for C16H30NO2: 268.2277; found:
(12), 57 (40).
268.2292.
HRMS (ESI): m/z [M + H]+ calcd for C19H28NO3: 318.2069; found:
318.2096.
tert-Butyl (R)-Allyl[(2S)-2-(tert-butyldimethylsiloxy)hex-5-en-
3-yl]carbamate (4g)
Following the general procedure, 9g (1.10 g, 4.1 mmol) was con-
verted into 4g (0.83 g, 2.2 mmol, 54%); colorless liquid.
[α]D25 +4.3 (c 0.25, CH2Cl2).
tert-Butyl Allyl[1-(4-benzyloxyphenyl)but-3-enyl]carbamate
(4d)
Following the general procedure, 9d (1.28 g, 4.4 mmol) was con-
verted into 4d (1.13 g, 2.9 mmol, 66%); colorless liquid.
IR (ATR): 3078 (w), 2931 (w), 1692 (s), 1365 (s), 1251 (s), 1153
(s), 833 (s), 773 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 5.98–5.64 (m, 2 H), 5.16–4.96 (m,
4 H), 4.08–3.85 (m, 3 H), 3.77 (m, 1 H), 2.46 (m, 1 H), 2.25 (m, 1
H), 1.43 (br s, 9 H), 1.12 (d, J = 6.2 Hz, 3 H), 0.89 (s, 9 H), 0.05 (s,
3 H), 0.04 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 156.3, 155.9, 137.0, 135.9, 116.6,
115.1, 79.5, 79.2, 70.9, 70.7, 60.5, 48.3, 34.6, 34.4, 28.5, 27.5, 25.9,
21.0, 17.9, –4.2, –5.0.
IR (ATR): 2975 (w), 1684 (s), 1510 (s), 1394 (s), 1233 (s), 1170 (s),
1141 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.48–7.29 (m, 5 H), 7.25 (d,
J = 8.7 Hz, 2 H), 6.93 (dm, J = 8.8 Hz, 2 H), 5.81 (ddt, J = 17.0,
10.2, 6.8 Hz, 2 H), 5.61 (br m, 1 H), 5.12 (ddt, J = 17.2, 1.7, 1.4 Hz,
1 H), 5.08–5.02 (m, 1 H), 5.06 (br s, 2 H), 5.01–4.87 (m, 2 H), 3.76–
3.38 (m, 2 H), 2.69 (dm, J = 7.4 Hz, 2 H), 1.47 (br s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 158.0, 155.7, 137.0, 135.9, 135.3,
132.7, 129.1, 128.6, 127.9, 127.4, 117.0, 115.6, 114.6, 79.7, 70.0,
57.6, 46.2, 35.8, 28.5.
MS (EI): m/z (%) = 256 (34), 210 (31), 154 (100), 110 (73), 73 (31),
57 (90), 41 (30).
MS (EI): m/z (%) = 352 (18), 296 (92), 252 (26), 91 (100), 57 (77),
41 (20).
HRMS (ESI): m/z [M + Na]+ calcd for C25H31NO3Na: 416.2202;
found: 416.2227.
HRMS (ESI): m/z [M + H]+ calcd for C20H40NO3Si: 370.2777;
found: 370.2752.
Anal. Calcd for C20H39NO3Si (369.61): C, 65.0; H, 10.6; N, 3.8.
Found: C, 64.9; H, 10.5; N, 3.8.
Anal. Calcd for C25H31NO3 (393.52): C, 76.3; H, 7.9; N, 3.6. Found:
C, 76.0; H, 8.3; N, 4.2.
tert-Butyl 6-Phenyl-5,6-dihydropyridine-1(2H)-carboxylate
(5a)
To a solution of 4a (200 mg, 0.70 mmol) in anhyd and degassed tol-
uene (7 mL) was added 2nd generation Grubbs catalyst B (14.9 mg,
2.5 mol%). The mixture was heated to 80 °C for 2 h, cooled to r.t.,
and evaporated. The residue was chromatographed to furnish 5a
(157 mg, 0.61 mmol, 87%); colorless liquid.
tert-Butyl Allyl[1-(1,4-dioxaspiro[4.5]decan-2-yl)but-3-
enyl]carbamate (4e)
Following the general procedure, 9e (0.62 g, 2.5 mmol) was con-
verted into 4e (0.80 g, 2.30 mmol, 92%); colorless liquid. Analytical
data of the major diastereomer were obtained from the mixture.
IR (ATR): 3078 (w), 2934 (m), 1689 (s), 1365 (m), 1249 (m), 1162
(s), 1100 (s), 909 cm–1 (s).
IR (ATR): 3451 (w), 2974 (w), 1690 (s), 1407 (s), 1360 (s), 1165
(s), 1107 (s), 698 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 5.97–5.60 (m, 2 H), 5.07 (ddm,
J = 18.2, 10.4 Hz, 2 H), 5.07 (ddm, J = 17.4, 9.5 Hz, 2 H), 4.23–
4.02 (m, 2 H), 3.98 (dd, J = 8.1, 6.1 Hz, 1 H), 3.94–3.67 (m, 2 H),
3.58 (dd, J = 7.8, 7.8 Hz, 1 H), 2.42 (m, 1 H), 2.17 (m, 1 H), 1.67–
1.48 (m, 8 H), 1.43 (br s, 9 H), 1.40–1.31 (m, 2 H).
1H NMR (300 MHz, CDCl3): δ = 7.32–7.19 (m, 5 H), 5.88 (ddd,
J = 10.1, 4.6, 2.2 Hz, 1 H), 5.64 (dm, J = 10.0 Hz, 1 H), 5.54 (dm,
J = 5.3 Hz, 1 H), 4.22 (dm, J = 18.3 Hz, 1 H), 3.34 (ddm, J = 18.6,
4.8 Hz, 1 H), 2.71 (ddm, J = 17.6, 6.3 Hz, 1 H), 2.56 (ddm, J = 17.6,
4.5 Hz, 1 H), 1.50 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 156.0, 136.5, 134.8, 117.2, 115.2,
109.3, 79.5, 76.2, 66.5, 56.9, 48.2, 36.2, 34.7, 34.2, 28.4, 25.2, 24.0,
23.8.
13C NMR (75 MHz, CDCl3): δ = 155.1, 141.1, 128.2, 126.9, 126.7,
124.5, 123.2, 79.8, 50.7, 40.3, 28.4.
MS (EI): m/z = 259 (1, [M]+), 158 (7), 104 (9), 77 (12), 57 (100), 41
(27).
MS (EI): m/z (%) = 352 (1, [M + H]+), 252 (17), 210 (43), 154
(100), 110 (49), 57 (58), 41 (24).
HRMS (EI): m/z [M]+ calcd for C16H21NO2: 259.1572; found:
259.1577.
Synthesis 2014, 46, 1648–1658
© Georg Thieme Verlag Stuttgart · New York

PAPER
Sequential RCM Isomerization
1655
Anal. Calcd for C16H21NO2 (259.34): C, 74.1; H, 8.2; N, 5.4. Found:
C, 73.9; H, 8.2; N, 5.5.
MS (EI): m/z (%) = 254 (22), 236 (26), 208 (40), 193 (54), 180 (74),
162 (67), 147 (72), 136 (92), 57 (100), 41 (57).
HRMS (ESI): m/z [M + H]+ calcd for C17H24NO3: 290.1756; found:
290.1768.
Cyclic Enamides 6; General Procedure
To a solution of the appropriate N-Boc-protected precursor 4 (1.0
equiv) in anhyd and degassed toluene (10 mL/mmol) was added 2nd
generation Grubbs catalyst B (2.5 mol%). The solution was heated
to 80 °C until the starting material was fully consumed (TLC, ca. 2
h). Solid NaOH 1.5 equiv) was then added, and the mixture was
heated to reflux for 16 h. The mixture was cooled to r.t., H2O was
added, and the aqueous layer was separated and extracted with t-
BuOMe (3 ×). The combined organic extracts were dried (MgSO4),
filtered, and evaporated. The residue was purified by chromatogra-
phy (silica gel) to furnish the cyclic enamides 6.
Anal. calcd for C17H23NO3 (289.37): C, 70.6; H, 8.0; N, 4.8. Found:
C, 70.5; H, 8.2; N, 4.9.
tert-Butyl 2-(4-Benzyloxyphenyl)-3,4-dihydropyridine-1(2H)-
carboxylate (6d)
Following the general procedure, 4d (197 mg, 0.50 mmol) was con-
verted into 6d (151 mg, 0.41 mmol, 83%); colorless oil.
IR (ATR): 2975 (w), 1699 (s), 1509 (s), 1349 (s), 1238 (s), 1169 (s),
736 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.49–7.29 (m, 5 H), 7.12 (d,
J = 8.5 Hz, 2 H), 7.03 (br m, 1 H), 6.94 (d, J = 8.8 Hz, 2 H), 5.34 (br
m, 1 H), 5.05 (s, 2 H), 5.90 (br m, 1 H), 2.16–1.67 (m, 4 H), 1.64–
1.20 (m, 9 H).
13C NMR (75 MHz, CDCl3): δ = 157.5, 152.6, 137.1, 134.7, 128.4,
127.8, 127.4, 126.5, 125.2, 114.6, 105.2, 80.5, 70.0, 53.8, 28.1,
27.6, 17.1.
tert-Butyl 2-Phenyl-3,4-dihydropyridine-1(2H)-carboxylate
(6a)
Following the general procedure, 4a (200 mg, 0.70 mmol) was con-
verted into 6a (153 mg, 0.59 mmol, 84%); colorless solid; mp 70–
72 °C.
IR (ATR): 2975 (w), 1703 (s), 1653 (m), 1347 (s), 1168 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.35–7.13 (m, 5 H), 7.05 (br m, 1
H), 5.33 (br m, 1 H), 4.91 (br m, 1 H), 2.11–1.95 (m, 2 H), 1.88 (m,
1 H), 1.73 (m, 1 H), 1.60–1.13 (9 H).
MS (EI): m/z (%) = 365 (3, [M]+), 309 (6), 256 (7), 174 (6), 91
(100), 57 (19), 41 (9).
HRMS (ESI): m/z [M + Na]+ calcd for C23H27NO3Na: 388.1889;
found: 388.1882.
13C NMR (125 MHz, CDCl3): δ = 152.8, 152.2, 142.8, 141.7, 128.2,
126.6, 125.4, 125.1, 105.5, 105.2, 80.8, 80.5, 55.1, 53.5, 28.3, 28.0,
27.6, 27.4, 17.2, 17.0.
Anal. Calcd for C23H27NO3 (365.47): C, 75.6; H, 7.5; N, 3.8. Found:
C, 75.2; H, 7.5; N, 3.9.
MS (EI): m/z (%) = 259 (10, [M]+), 203 (100), 186 (13), 158 (40),
142 (55), 104 (37), 57 (50).
HRMS (EI): m/z [M + H]+ calcd for C16H22NO2: 260.1651; found:
260.1655.
tert-Butyl 2-(1,4-Dioxaspiro[4.5]decan-2-yl)-3,4-dihydropyri-
dine-1(2H)-carboxylate (6e)
Following the general procedure, 4e (246 mg, 0.70 mmol) was con-
verted into 6e (86 mg, 0.27 mmol, 39%); colorless oil.
Anal. Calcd for C16H21NO2 (259.34): C, 74.1; H, 8.2; N, 5.4. Found:
C, 74.0; H, 8.3; N, 5.4.
IR (ATR): 2933 (s), 1700 (s), 1653 (m), 1361 (s), 1164 (s), 1115 (s),
927 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 6.83 (br m, 1 H), 4.83 (br m, 1 H),
4.40–4.15 (m, 2 H), 4.01 (dd, J = 8.0, 6.3 Hz, 1 H), 3.67 (br m, 1 H),
2.17–1.88 (m, 2 H), 1.88–1.69 (m, 2 H), 1.65–1.20 (m, 19 H).
13C NMR (75 MHz, CDCl3): δ = 152.5, 124.8, 109.7, 104.8, 80.4,
75.2, 66.3, 51.6, 36.0, 35.1, 28.2, 25.2, 23.9, 23.9, 23.2, 18.5.
tert-Butyl 2-(4-Bromophenyl)-3,4-dihydropyridine-1(2H)-car-
boxylate (6b)
Following the general procedure, 4b (183 mg, 0.50 mmol) was con-
verted into 6b (135 mg, 0.40 mmol, 80%); colorless solid; mp 62–
65 °C.
IR (ATR): 2977 (w), 1698 (s), 1366 (s), 1158 (s), 828 (w) cm–1.
MS (EI): m/z (%) = 323 (16, [M]+), 223 (58), 141 (19), 108 (20), 82
(100), 57 (39), 41 (15).
HRMS (EI): m/z [M]+ calcd for C18H29NO4: 323.2097; found:
323.2093.
1H NMR (300 MHz, CDCl3): δ = 7.41 (dm, J = 8.5 Hz, 2 H), 7.03
(dm, J = 8.3 Hz, 2 H), 6.94 (br m, 1 H), 5.26 (br m, 1 H), 4.89 (br
m, 1 H), 2.10–1.58 (m, 4 H), 1.57–1.21 (m, 9 H).
13C NMR (75 MHz, CDCl3): δ = 131.4 (1), 127.3 (1), 125.2 (1),
120.4 (0), 105.4 (1), 80.9 (0), 28.2 (3), 27.4 (2), 17.0 (2).
tert-Butyl 2-Isobutyl-3,4-dihydropyridine-1(2H)-carboxylate
(6f)
Following the general procedure, 4f (250 mg, 0.94 mmol) was con-
verted into 6f (174 mg, 0.73 mmol, 77%); colorless oil.
MS (EI): m/z (%) = 286 (10), 284 (13), 228 (15), 184 (20), 85 (14),
83 (18), 57 (100), 41 (32).
HRMS (ESI): m/z [M + H]+ calcd for C16H21NO2Br: 338.0756;
found: 338.0781.
IR (ATR): 2956 (m), 1700 (s), 1651 (s), 1360 (s), 1171 (s), 1121 (s),
767 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 6.71 (d, J = 7.9 Hz, 1 H), 4.80 (br
m, 1 H), 4.28 (br m, 1 H), 2.12–1.85 (m, 2 H), 1.85–1.51 (m, 3 H),
1.47 (br s, 9 H), 1.31 (m, 2 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.89 (d,
J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 152.6, 152.1, 124.4, 124.0, 105.1,
104.6, 80.2, 48.8, 47.7, 39.8, 39.3, 28.3, 24.5, 24.4, 24.1, 23.5, 22.0,
17.7, 17.5.
MS (EI): m/z (%) = 239 (2, [M]+), 183 (5), 127 (12), 82 (34), 57
(100), 41 (42).
HRMS (EI): m/z [M]+ calcd for C14H25NO2: 239.1885; found:
239.1875.
Anal. Calcd for C16H20NO2Br (338.24): C, 56.8; H, 6.0; N, 4.1.
Found: C, 56.8; H, 6.2; N, 4.1.
tert-Butyl 2-(4-Methoxyphenyl)-3,4-dihydropyridine-1(2H)-
carboxylate (6c)
Following the general procedure, 4c (159 mg, 0.50 mmol) was con-
verted into 6c (93 mg, 0.32 mmol, 64%); colorless oil.
IR (ATR): 2975 (w), 1698 (s), 1513 (s), 1351 (s), 1247 (s), 1168 (s),
834 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.07 (d, J = 8.5 Hz, 2 H), 6.97 (br
m, 1 H), 6.82 (d, J = 8.8 Hz, 2 H), 5.29 (br m, 1 H), 4.90 (br m, 1
H), 3.77 (s, 3 H), 2.10–1.63 (m, 4 H), 1.62–1.18 (m, 9 H).
13C NMR (75 MHz, CDCl3): δ = 158.3, 152.7, 134.9, 126.5, 125.3,
Anal. Calcd for C14H25NO2 (239.35): C, 70.3; H, 10.5; N, 5.9.
Found: C, 70.0; H, 10.5; N, 5.7.
113.6, 105.3, 80.6, 55.2, 54.5–53.0 (br), 28.1, 27.6, 17.1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1648–1658

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B. Schmidt et al.
PAPER
tert-Butyl (R)-2-[(S)-1-(tert-Butyldimethylsiloxy)ethyl]-3,4-di-
hydropyridine-1(2H)-carboxylate (6g)
Following the general procedure, 4g (259 mg, 0.70 mmol) was con-
verted into 6g (198 mg, 0.58 mmol, 83%); colorless solid; mp
68 °C.
13C NMR (75 MHz, CDCl3): δ = 199.1, 155.8, 136.1, 128.5, 128.2,
128.0, 67.0, 55.8, 14.7.
MS (EI): m/z (%) = 208 (4, [M + H]+), 178 (21), 134 (12), 91 (100),
65 (9).
HRMS (ESI): m/z [M + H]+ calcd for C11H14NO3: 208.0974; found:
208.0953.
24
[α]D D –29.1 (c 0.78, CH2Cl2).
IR (ATR): 2930 (m), 2857 (m), 1703 (s), 1651 (m), 1349 (s), 1251
(s), 1174 (s), 1114 (s), 832 (s), 774 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 6.77 (br m, 1 H), 4.79 (br m, 1 H),
4.12 (br m, 1 H), 3.89 (dq, J = 8.4, 6.2 Hz, 1 H), 2.01–1.86 (m, 3 H),
1.78–1.59 (m, 1 H), 1.47 (br s, 9 H), 1.14 (d, J = 6.2 Hz, 3 H), 0.86
(s, 9 H), 0.01 (s, 3 H), –0.01 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 152.5, 125.3, 104.9, 80.2, 66.5,
55.0, 28.4, 25.9, 22.2, 20.6, 18.6, 18.0, –4.7, –4.9.
MS (EI): m/z (%) = 341 (2, [M]+), 228 (75), 184 (17), 159 (16), 126
(21), 82 (100), 73 (46), 57 (52).
Anal. Calcd for C11H13NO3 (207.23): C, 63.8; H, 6.3; N, 6.8. Found:
C, 63.5; H, 6.2; N, 6.7.
tert-Butyl (2S)-3-Hydroxypent-4-en-2-ylcarbamate (13a)
A solution of 12a (240 mg, 1.40 mmol) in anhyd and degassed
CH2Cl2 (50 mL) was cooled to 0 °C. 1.6 M Vinylmagnesium chlo-
ride in THF (2.00 mL, 3.2 mmol) was added and the mixture was
stirred at 0 °C for 2 h. The mixture was quenched by the addition of
sat. aq NH4Cl. The aqueous layer was separated and extracted t-
BuOMe (2 ×), the combined organic extracts were dried (MgSO4),
filtered, and evaporated. The residue was purified by column chro-
matography (silica gel) to give 13a (207 mg, 1.00 mmol, 74%); 4:1
mixture of diastereomers; colorless liquid.
HRMS (EI): m/z [M]+ calcd for C18H35NO3Si: 341.2386; found:
341.2393.
IR (ATR): 3353 (m), 2977 (m), 1684 (s), 1504 (s), 1366 (s), 1246
(s), 1165 (s), 1050 cm–1 (s).
Anal. Calcd for C18H35NO3Si (341.56): C, 63.3; H, 10.3; N, 4.1.
Found: C, 63.2; H, 10.3; N, 4.0.
1H NMR (300 MHz, CDCl3): δ = 5.86 (ddd, J = 17.0, 10.4, 6.1 Hz,
1 H), 5.29 (ddd, J = 17.2, 1.3, 1.2 Hz, 1 H), 5.18 (dm, J = 10.4 Hz,
1 H), 4.72 (d, J = 3.9 Hz, 1 H), 4.00 (dm, J = 5.9 Hz, 1 H), 3.68 (qm,
J = 6.8 Hz, 1 H), 2.71 (br s, 1 H), 1.42 (s, 9 H), 1.15 (d, J = 6.8 Hz,
3 H).
13C NMR (75 MHz, CDCl3): δ = 184.5 (0), 138.0 (1), 116.5 (2),
79.5 (0), 76.2 (1), 50.7 (1), 28.4 (3), 17.5 (3).
MS (EI): m/z (%) = 202 (11, [M + H]+), 146 (39), 144 (47), 128
(17), 88 (33), 57 (100), 44 (49).
HRMS (ESI): m/z [M + H]+ calcd for C10H20NO3: 202.1443; found:
202.1447.
tert-Butyl (S)-1-Oxopropan-2-ylcarbamate (12a)
A solution of 11a (406 mg, 2.00 mmol) in anhyd and degassed
CH2Cl2 (50 mL) was cooled to –78 °C. 1.01 M DIBAL-H in cyclo-
hexane (6.0 mL, 6.1 mmol) was added dropwise and the solution
was stirred at –78 °C until the starting material was fully consumed
(TLC, ca. 0.75 h). MeOH (5 mL) was added at –78 °C, the solution
was then warmed to r.t., and poured into sat. aq sodium potassium
tartrate solution. The aqueous layer was separated and extracted
with Et2O (3 ×), and the combined organic layers were dried
(MgSO4), filtered, and evaporated. The residue was purified by col-
umn chromatography to give 12a (331 mg, 1.90 mmol, 96%); col-
orless solid; mp 84–85 °C.
Anal. Calcd for C10H19NO3 (201.26): C, 59.7; H, 9.5; N, 7.0. Found:
C, 59.4; H, 9.3; N, 7.0.
[α]D23 +14.2 (c 0.46, CH2Cl2).
IR (ATR): 3331 (m), 2980 (m), 1728 (s), 1681 (s), 1528 (s), 1366
(s), 1249 (s), 1164 (s), 1057 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 9.55 (s, 1 H), 5.10 (br s, 1 H), 4.22
(br s, 1 H), 1.45 (s, 9 H), 1.33 (d, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 199.7, 155.2, 80.1, 55.5, 28.3,
14.8.
MS (EI): m/z (%) = 174 (6, [M + H]+), 161 (7), 144 (40), 118 (16),
88 (49), 74 (13), 57 (100), 44 (42).
HRMS (ESI): m/z [M + Na]+ calcd for C8H15NO3Na: 196.0950;
found: 196.0961.
Benzyl (2S)-3-Hydroxypent-4-en-2-ylcarbamate (13b)
Following the procedure for the synthesis of 13a, aldehyde 12b
(900 mg, 4.30 mmol) was converted into 13b (705 mg, 3.00 mmol,
70%); 4:1 mixture of diastereomers; colorless liquid.
IR (ATR): 3442 (m), 2932 (w), 1694 (s), 1513 (s), 1218 (s), 1051
(s), 750 (s), 696 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.42–7.28 (m, 5 H), 5.88 (ddd,
J = 16.9, 10.4, 6.1 Hz, 1 H), 5.30 (ddd, J = 17.2, 1.3, 1.3 Hz, 1 H),
5.20 (ddd, J = 10.4, 1.2, 1.2 Hz, 1 H), 5.09 (m, 1 H), 5.10 (s, 2 H),
4.05 (m, 1 H), 3.80 (qm, J = 6.8 Hz, 1 H), 2.63 (br s, 1 H), 1.20 (d,
J = 6.8 Hz, 3 H).
Anal. Calcd for C8H15NO3 (173.21): C, 55.5; H, 8.7; N, 8.1. Found:
C, 55.9; H, 8.4; N, 7.9.
13C NMR (75 MHz, CDCl3): δ = 156.5, 137.7, 136.4, 128.4, 128.0,
128.0, 116.7, 75.6, 66.7, 51.0, 17.5.
MS (EI): m/z (%) = 236 (5, [M + H]+), 178 (15), 134 (17), 91 (100),
65 (10).
HRMS (ESI): m/z [M + H]+ calcd for C13H18NO3: 236.1287; found:
236.1272.
Benzyl (S)-1-Oxopropan-2-ylcarbamate (12b)
A solution of 11b (12.30 g, 51.7 mmol) in anhyd and degassed
CH2Cl2 (200 mL) was cooled to –78 °C. 1.01 M DIBAL-H in cyclo-
hexane (103 mL, 114 mmol) was added dropwise and the solution
was stirred for 0.75 h (TLC control). The reaction was quenched at
–78 °C by addition of MeOH (50 mL), warmed to r.t., and poured
into sat. aq sodium potassium tartrate solution. Workup and purifi-
cation as described for 12a furnished 12b (9.70 g, 46.8 mmol, 91%);
colorless liquid.
tert-Butyl (2S)-3-(Methoxymethoxy)pent-4-en-2-ylcarbamate
(14a)
To a solution of 13a (201 mg, 1.00 mmol) in anhyd and degassed
CH2Cl2 (10 mL) was added i-Pr2NEt (0.26 mL, 1.50 mmol),
MOMBr (technical grade, 90%, 0.12 mL, 1.30 mmol), and DMAP
(24 mg, 0.20 mmol). The mixture was stirred for 16 h at 40 °C,
cooled to r.t., and hydrolyzed by addition of a sat. aq NH4Cl. The
aqueous layer was separated and repeatedly extracted with t-
BuOMe, and the combined organic extracts were dried (MgSO4),
filtered, and evaporated. Purification by column chromatography
[α]D23 +9.9 (c 0.75, CH2Cl2).
IR (ATR): 3327 (m), 2940 (w), 1693 (s), 1517 (s), 1454 (m), 1239
(s), 1051 (s), 737 (s), 696 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 9.45 (s, 1 H), 7.42–7.26 (m, 5 H),
5.50 (br s, 1 H), 5.11 (s, 2 H), 4.26 (q, J = 7.1 Hz, 1 H), 1.35 (d,
J = 7.1 Hz, 3 H).
Synthesis 2014, 46, 1648–1658
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PAPER
Sequential RCM Isomerization
1657
(silica gel) furnished 14a (192 mg, 0.80 mmol, 79%); colorless liq-
uid.
Anal. Calcd for C15H27NO4 (285.38): C, 63.1; H, 9.5; N, 4.9. Found:
C, 63.2; H, 9.5; N, 5.0.
IR (ATR): 2976 (m), 1707 (s), 1158 (s), 1028 (s), 920 cm–1 (m).
Benzyl Allyl[(2S,3S)-3-(benzyloxymethoxy)pent-4-en-2-yl]car-
bamate (4i)
Following the procedure for the synthesis of 4h, the Cbz-protected
amine 14b (178 mg, 0.50 mmol) was converted into 4i (176 mg,
0.45 mmol, 90%); colorless liquid.
1H NMR (300 MHz, CDCl3): δ = 5.70 (ddd, J = 16.9, 12.0, 7.5 Hz,
1 H), 5.32–5.19 (m, 2 H), 4.66 (d, J = 6.7 Hz, 1 H), 4.52 (d, J = 6.7
Hz, 1 H), 3.94 (qd, J = 7.5, 3.7 Hz, 1 H), 3.78 (m, 1 H), 3.36 (s, 3
H), 1.41 (s, 9 H), 1.15 (d, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 155.4 (0), 134.9 (1), 118.9 (2),
94.0 (2), 79.4 (1), 55.6 (3), 49.5 (1), 28.3 (3), 17.6 (3).
IR (ATR): 2942 (w), 1695 (s), 1408 (m), 1242 (m), 1025 (s), 734
(s), 696 cm–1 (s).
1H NMR (500 MHz, CDCl3): δ = 7.42–7.27 (m, 10 H), 5.86 (m, 1
H), 5.64 (m, 1 H), 5.37–5.03 (m, 6 H), 4.80–4.57 (m, 3 H), 4.45 (d,
J = 11.9 Hz, 1 H), 4.30–4.02 (m, 2 H), 4.02–3.74 (m, 2 H), 1.22 (d,
J = 7.1 Hz, 3 H).
MS (EI): m/z (%) = 202 (50), 158 (19), 88 (53), 57 (100), 44 (74).
HRMS (ESI): m/z [M + H]+ calcd for C12H24NO4: 246.1705; found:
246.1686.
Anal. Calcd for C12H23NO4 (245.32): C, 58.8; H, 9.5; N, 5.7. Found:
C, 58.7; H, 9.4; N, 5.7.
13C NMR (125 MHz, CDCl3): δ = 156.1, 137.8, 136.8, 135.6, 135.3,
128.4, 127.8, 127.7, 127.6, 119.6, 115.8, 91.7, 79.3, 69.4, 66.9,
55.7, 47.6, 15.5.
Benzyl (2S)-3-(Benzyloxymethoxy)pent-4-en-2-ylcarbamate
(14b)
MS (EI): m/z (%) = 396 (4, [M + H]+), 288 (6), 218 (30), 174 (28),
Following the procedure for the synthesis of 14a, the alcohol 13b
(650 mg, 2.80 mmol) and BOMCl (technical grade 90%, 1.0 mL,
7.20 mmol) were converted into 14b (725 mg, 2.04 mmol, 74%);
colorless liquid.
91 (100).
HRMS (ESI): m/z [M + Na]+ calcd for C24H29NO4Na: 418.1994;
found: 418.2007.
IR (ATR): 3337 (w), 2940 (w), 1706 (s), 1498 (s), 1228 (s), 1025
(s), 737 (s), 697 cm–1 (s).
tert-Butyl (2S,3S)-3-(Methoxymethoxy)-2-methyl-3,4-dihydro-
pyridine-1(2H)-carboxylate (6h)
Following the general procedure for the RCM–isomerization se-
quence, 4h (483 mg, 1.69 mmol) was converted into 6h (395 mg,
1.54 mmol, 91%); colorless liquid.
1H NMR (300 MHz, CDCl3): δ = 7.42–7.27 (m, 10 H), 5.75 (ddd,
J = 17.6, 9.9, 7.7 Hz, 1 H), 5.40–5.25 (m, 2 H), 5.12 (s, 2 H), 4.97
(m, 1 H), 4.79 (d, J = 6.7 Hz, 1 H), 4.72 (d, J = 6.8 Hz, 1 H), 4.71
(dm, J = 11.5 Hz, 1 H), 4.53 (dd, J = 11.8, 1.5 Hz, 1 H), 4.07 (dd,
J = 7.1, 2.9 Hz, 1 H), 3.93 (m, 1 H), 1.24 (d, J = 6.7 Hz, 3 H).
[α]D23 +13.3 (c 0.42, CH2Cl2).
IR (ATR): 2929 (m), 1702 (s), 1345 (s), 1270 (s), 1102 (s), 1045
cm–1 (s).
13C NMR (75 MHz, CDCl3): δ = 155.9, 137.6, 136.6, 134.7, 128.5,
1H NMR (300 MHz, CDCl3): δ = 6.63 (d, J = 7.6 Hz, 1 H), 4.74 (m,
1 H), 4.68 (s, 2 H), 4.35 (m, 1 H), 3.84 (qd, J = 5.7, 4.9 Hz, 1 H),
3.37 (s, 3 H), 2.26 (ddd, J = 16.9, 5.9, 5.7 Hz, 1 H), 2.08 (dddd,
J = 16.8, 10.6, 2.5, 2.4 Hz, 1 H), 1.47 (s, 9 H), 1.04 (d, J = 6.6 Hz,
3 H).
128.4, 128.0, 127.8, 127.7, 119.4, 91.9, 79.5, 69.7, 66.6, 50.2, 17.9.
MS (EI): m/z (%) = 281 (3), 127 (12), 99 (25), 91 (100), 85 (52), 71
(82), 57 (99), 43 (47).
HRMS (ESI): m/z [M + H]+ calcd for C21H26NO4: 356.1862; found:
356.1835.
13C NMR (75 MHz, CDCl3): δ = 152.2, 151.6, 123.9, 123.6, 101.4,
tert-Butyl Allyl[(2S,3S)-3-(methoxymethoxy)pent-4-en-2-
yl]carbamate (4h)
95.4, 95.3, 80.7, 80.7, 72.4, 72.1, 55.4, 49.7, 48.3, 28.3, 25.1, 10.7.
MS (EI): m/z (%) = 257 (33, [M]+), 201 (16), 141 (62), 124 (43),
112 (39), 97 (100), 82 (70), 57 (81), 45 (38).
HRMS (EI): m/z [M]+ calcd for C13H23NO4: 257.1622; found:
To a solution of 14a (1.95 g, 8.0 mmol) in anhyd and degassed THF
(100 mL) was added NaH (dispersion in mineral oil 60 wt%, 0.95
mg, 23.9 mmol), allyl bromide (1.37 mL, 15.9 mmol), and TBAI
(294 mg, 0.80 mmol). The mixture was heated to reflux and stirred
for 3 h and then cooled to r.t. The mixture was carefully poured into
H2O, and the aqueous layer was separated and repeatedly extracted
with t-BuOMe. The combined organic layers were dried (MgSO4),
filtered, and evaporated. The residue was purified by chromatogra-
phy (silica gel) to give 4h (1.24 g, 4.4 mmol, 55%); single diaste-
reomer; colorless liquid.
257.1633.
Benzyl (2S,3S)-3-(Benzyloxymethoxy)-2-methyl-3,4-dihydro-
pyridine-1(2H)-carboxylate (6i)
Following the general procedure for the RCM–isomerization se-
quence, 4i (277 mg, 0.70 mmol) was converted into 6i (203 mg,
0.56 mmol, 79%); colorless liquid.
[α]D25 –2.1 (c 0.30, CH2Cl2).
[α]D24 +44.1 (c 0.33, CH2Cl2).
IR (ATR): 2890 (w), 1702 (s), 1654 (m), 1408 (s), 1337 (s), 1260
(s), 1038 (s), 732 (s), 696 cm–1 (s).
IR (ATR): 2977 (m), 1690 (s), 1365 (s), 1155 (s), 1029 (s), 919 (s),
773 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 5.80 (m, 1 H), 5.62 (m, 1 H), 5.30–
5.19 (m, 2 H), 5.18–4.98 (m, 2 H), 4.63 (d, J = 6.8 Hz, 1 H), 4.48
(m, 1 H), 4.25–3.89 (m, 2 H), 3.89–3.62 (m, 2 H), 3.33 (s, 3 H), 1.44
(br s, 9 H), 1.14 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 155.5, 136.2, 135.9, 135.7, 119.0,
115.5, 115.1, 93.9, 79.4, 79.2, 55.6, 55.5, 54.5, 48.7, 47.4, 28.4,
16.1, 15.5.
1H NMR (300 MHz, CDCl3): δ = 7.42–7.27 (m, 10 H), 6.72 (d,
J = 8.0 Hz, 1 H), 5.31–5.11 (m, 2 H), 4.83 (s, 2 H), 4.75 (ddd,
J = 7.7, 5.7, 5.3 Hz, 1 H), 4.64 (s, 2 H), 4.51 (dt, J = 6.0, 5.6 Hz, 1
H), 3.96 (m, 1 H), 2.31 (ddd, J = 17.1, 5.6, 5.4 Hz, 1 H), 2.13 (dddd,
J = 17.1, 10.6, 2.5, 2.4 Hz, 1 H), 1.12 (d, J = 6.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 152.6, 137.6, 136.2, 128.5, 128.4,
128.1, 128.0, 127.8, 123.6, 123.2, 102.8, 93.7, 93.2, 72.4, 71.8,
69.8, 69.7, 67.6, 67.5, 49.6, 49.0, 25.0, 24.8, 11.3, 10.7.
MS (EI): m/z (%) = 267 (19), 184 (30), 128 (82), 98 (73), 84 (100),
71 (73), 56 (94), 41 (45).
HRMS (ESI): m/z [M + H]+ calcd for C15H28NO4: 286.2018; found:
286.1998.
MS (EI): m/z (%) = 396 (2, [M]+), 232 (8), 170 (6), 91 (100).
HRMS (EI): m/z [M]+ calcd for C22H25NO4: 367.1784; found:
367.1773.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1648–1658

1658
B. Schmidt et al.
PAPER
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Acknowledgment
Generous financial support of this work by the Deutsche For-
schungsgemeinschaft (DFG grant Schm1095/6-2) is gratefully
acknowledged. We thank Evonik oxeno for donations of solvents.
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Synthesis 2014, 46, 1648–1658
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