Enantioselective Synthesis of Pyrrolizin-1-ones via Lewis Base Catalyzed N-Allylation of N-Silyl Pyrrole Latent Nucleophiles

Article abstract of DOI:10.1021/acs.joc.9b02819

Pyrrolizidine alkaloids and their derivatives often feature interesting biological activities. A class of substituted 2,3-dihydro-1H-pyrrolizin-1-one derivatives has been explored as a potential treatment for Alzheimer's disease, but enantioselective synthesis of these molecules is still elusive. We report that enantioselective N-allylation of N-silyl pyrrole latent nucleophiles with allylic fluorides followed by hydrogenation and diastereoselective Friedel-Crafts cyclization constitute an efficient synthetic route to access enantioenriched substituted 2,3-dihydro-1H-pyrrolizin-1-ones.

Full text of DOI:10.1021/acs.joc.9b02819

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Enantioselective Synthesis of Pyrrolizin-1-ones via Lewis Base
Catalyzed N-Allylation of N-Silyl Pyrrole Latent Nucleophiles
Markus Lange, You Zi, and Ivan Vilotijevic
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02819 • Publication Date (Web): 05 Dec 2019
Downloaded from pubs.acs.org on December 5, 2019
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Enantioselective Synthesis of Pyrrolizin-1-ones via Lewis Base Catalyzed
N-Allylation of N-Silyl Pyrrole Latent Nucleophiles
Markus Lange, You Zi, Ivan Vilotijevic*
Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena,
Humboldtstr.10, 07743 Jena, Germany
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ivan.vilotijevic@uni-jena.de
F
O
Lewis base
catalyzed allylation
O
N
N
R
OMe
Reduction / Cyclization
TBS
R
latent
N-nucleophile
MBH
fluoride
enantioselective and
diastereoselective
pyrrolizin-1-ones
Abstract
Pyrrolizidine alkaloids and their derivatives often feature interesting biological activities. A class of
substituted 2,3-dihydro-1H-pyrrolizin-1-one derivatives has been explored as a potential treatment for
Alzheimer’s disease but enantioselective synthesis of these molecules is still elusive. We report that
enantioselective N-allylation of N-silyl pyrrole latent nucleophiles with allylic fluorides followed by
hydrogenation and diastereoselective Friedel-Crafts cyclization constitute an efficient synthetic route to
access enantioenriched substituted 2,3-dihydro-1H-pyrrolizin-1-ones.
Pyrrolizidine alkaloids are a large group of plant natural products with 1-azabicyclo[3.3.0]octane core.1
Many of these are toxic to humans and livestock and pose a significant threat to food safety. Other members
of the group exhibit medicinally relevant biological activity such as pochonicine (1, Scheme 1a) which has
2
been identified as a potent β‐N‐acetylglucosaminidase inhibitor. Among synthetic derivatives with different
levels of unsaturation and oxidation of the pyrrolizidine core, the derivatives with 2,3-dihydro-1H-pyrrolizine,
3
such as the dual COX/LOX inhibitor licofelon (2), have been under intense investigation and clinical
development. The ease of access to 1,2-dihydro-3H-pyrrolizin-3-ones (3) has prompted numerous SAR
4
studies of this scaffold. In contrast to this, synthetic approaches to 2,3-dihydro-1H-pyrrolizin-1-ones (4)
remain scarce despite the fact that this scaffold, due to its radical scavenging and anti-amyloid properties,
5
has recently been identified as a promising platform for treatment of Alzheimer’s disease. The reported
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synthetic approaches to this scaffold lack the control of stereoselectivity; the reactions proceed with low
diastereoselectivity and the products have not been prepared in enantioenriched form.5-6
Scheme 1. a) Some biologically active molecules/scaffolds derived from pyrrolizidine; b) Outline of our
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approach to enantioselective synthesis of substituted 2,3-dihydro-1H-pyrrolizin-1-ones
a) Biologically active molecules and scaffolds derived from pyrrolizines
HO
OH
Ph
H
HO
Cl
N
N
AcHN
, pochonicin
OH
COOH
1
2, licofelone

-N-acetylglucosaminidase inhibitor
COX inhibitor
2,3-dihydro-1H-pyrrolizine
pyrrolizidine
Ph
O
1
Ph
CO2Me
N
N 3
2
O
Ph
3
, anti-inflamatory agents
1,2-dihydro-3H-pyrrolizin-3-one
4, anti-amyloid agents
2,3-dihydro-1H-pyrrolizin-1-one
b) This work: Enantioselective approach to pyrrolizin-1-ones
O
1. enantioselective
allylic substitution
F
O
+
N
R
OMe
2
. hydrogenation
N
TBS
6
3. ring closure
R
5
7
Considering the possibility of easy epimerization at C2, we presumed that a successful enantioselective
approach to substituted 2,3-dihydro-1H-pyrrolizin-1-ones would have to effectively construct the C3
stereogenic center and allow for good control of diastereoselectivity at the C2 center. We have recently
reported a Lewis base catalyzed enantioselective N-allylation of pyrroles, indoles and carbazoles which
7
benefits from the concept of latent nucleophiles in Lewis base catalysis. As these reactions construct a
stereogenic center α to the nitrogen of the pyrrole and install the carbonyl group of the ester in an
appropriate position, we saw this as an opportunity to develop a short enantioselective synthesis of
substituted 2,3-dihydro-1H-pyrrolizin-1-ones. Here, we report the development of a short route to this
scaffold that consists of enantioselective N-allylation of N-silyl pyrroles followed by reduction and
diastereoselective cyclization (Scheme 1b).
Our work on Lewis base catalyzed N-allylation commenced as a proof of concept study for the use of latent
nucleophiles in Lewis base catalysis. This concept is aimed at expanding the scope for nucleophile and
8
allowing for better control of chemo-, regio- and stereoselectivity in Lewis base catalyzed reactions. It is a
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common occurrence that heteroatom nucleophiles compete and outperform the Lewis base catalyst thus
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preventing the development of enantioselective Lewis base catalyzed reactions. We hypothesized that
lowering the nucleophilicity of the nucleophilic reaction partner would increase the reaction selectivity and
allow flexibility in the choice of catalyst. For N-centered nucleophiles, introducing a silyl group at the nitrogen
atom lowers the nucleophilicity of the derivative (compared to the corresponding N-H nucleophile).10 Such
latent nucleophiles require an appropriate trigger to participate in the reaction. If activation of the nucleophile
depends on the activation of the electrophile, by mediacy of the leaving group from the electrophile, the
activated nucleophile is produced only when the activated electrophile is already present in the reaction
mixture allowing for the bimolecular reaction of the two activated reactants to outcompete other possible
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pathways. If activation of N-silyl latent nucleophile is to be dependent on activation of electrophile, mediacy
of a fluoride ion as a leaving group would be a suitable trigger which makes Morita-Baylis-Hillman derived
allylic fluorides a fitting reaction partner.
The reactions of various substituted allylic fluorides with N-TBS pyrrole have been evaluated in the
presence of catalytic amounts of DABCO (Scheme 2). This exercise demonstrated a broad electrophile
scope with reactions proceeding with good yields for both primary (8aa) and secondary allylic fluorides
regardless of their electronic properties (8ba-8va). The same is true for a variety of substituted pyrroles,
indoles and carbazoles (8ba-8bl). Electronically matched and mismatched sets of nucleophiles and
electrophiles performed equally well in these reactions with generally good yields (8kc, 8if, 8wi, 8jl, 8om,
8xi). Even sterically demanding nucleophiles/electrophiles, previously reported not to be reactive in related
reactions, performed reasonably well with yields of around 50% (8bk and 8wi).11 The reactions proceeded
N
with excellent regioselectivity: C2/C3 allylation of N-heterocycles and S 2’ type products were not observed
in any of the reactions.
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Scheme 2 N-allylation of N-silyl latent nucleophiles 6 with various allylic fluorides 5 in the presence of
DABCO. Isolated yields of the N-allyl pyrroles, indoles and carbazoles are shown. Conditions: 5 mol%
DABCO, 1.1 equiv. 6, CH
2
Cl
2
(0.1 M). Numbering scheme follows the following formula: 5x + 6y gives 8xy.
DABCO
(5 mol%)
F
R3
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CO2R2
R3
N
R1
CO R2
2
N
CH2Cl2, rt
R1
TBS
6
5
8
Scope for electrophiles (for R2 = Me, R3 = H)
R
8
ba, R = H, 96%
8ca, R = 4-Me, 83%
da, R = 4-tBu,79%
8ea, R = 3,5-diMe,84%
8ka, R = 4-CF3, 82%
8sa, 88%
8ta, 84%
8la, R = 4-NO2, 76%
8ma,R = 3-NO2, 75%
8na, R = 4-F, 68%
8oa, R = 4-Cl, 99%
8pa, R = 4-Br, 84%
8qa, R = 3-Br, 82%
8
8
8
8
8
fa, R = 4-OMe,77%
ga, R = 3-OMe, 79%
ha, R = 4-OTf, 80%
Ph
N
Tf
ia, R = 4-CO2Me, 92% 8ra, R = 4-I, 82%
8ua, 55%
8va, 71%
8ja, R = 4-CN, 92%
Scope for nucleophiles (for R1 = Ph, R2 = Me)
8
8
8
8
ba, R = H, 88% (1g scale)
8bf, R = H, 96%
R
N
bb, R = 2-CN, 81%
8bg, R = 5-NO2, 77%
8bh, R = 4-CN, 93%
8bi, R = 5-Br, 90%
8bj, R = 5-OMe, 90%
bc, R = 2-CO2Me, 67%
bd, R = 3-Bpin, 86%
R
N
N
8be, R = 3-Br, 82%
8bk, R = 2-Me, 47%
8bl, 82%
Br
Me
N
N
N
N
CO2Bn
H
CO2Bn
CO2Bn
CO2Bn
H
H
H
8aa, 83%
8ai, 83%
8af, 69%
8ak, 58%
Br
CO2Me
CO2Me
N
N
N
CO2Me
CO2Me
F3C
MeO2C
F
8kc, 72%
8if, 88%
CN
8wi, 44%
Br
N
N
N
CO2Me
CO2Me
CO2Me
NC
Cl
Br
8jl, 82%
8om, 77%
8xi, 83%
The comprehensive study of the reaction scope led into investigation of enantioselective N-allylation of
pyrrole in the presence of chiral Lewis base catalyst (Scheme 3). The cinchona alkaloid based catalysts,
well-established in similar allylic substitutions,12 performed well in these reactions too. (DHQD)
PHAL,
2
(DHQD)
2 2
AQN and (DHQ) PHAL all gave the desired products in good yields and good enantioselectivities.
The reactions proceed as kinetic resolutions of the racemic allylic fluorides,13 which is why the optimized
2
conditions included an excess of the allylic fluoride in the presence of 10 mol% of (DHQD) PHAL in
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trifluorotoluene at ambient temperature. The excess of allylic fluoride was required to offset the low reaction
rates caused by the significantly lower reactivity of the chiral catalysts and not to increase the
enantioselectivities suggesting that the reactions of the two enantiomeric allylic fluorides are
enantioconvergent. The enantiomeric ratios for pyrrole nucleophiles were generally higher than 90:10 and
a short, focused optimization of the reaction conditions for a specific substrate can be conducted to improve
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enantioselectivity. The yields remained good regardless of electronic properties of the allylic fluoride (45 -
83%, Scheme 3). The lowered reactivity of the catalyst also allowed for competitive elimination of the
fluoride from alkyl substituted allylic fluorides which led to lower yields (8ta’).
Scheme 3. Enantioselective allylic substitution with N-TBS pyrrole 6a. Isolated yields and enantiomeric
ratios determined by HPLC on chiral stationary phase are shown. Absolute configuration of the N-allyl
2
pyrroles 8 is assigned based analogy to previously reported material. Conditions: 10 mol% DHQD (PHAL),
2
equiv. of 5, PhCF
3
(0.2 M).
(DHQD)2PHAL
10 mol%)
F
(
N
CO2Me
N
R
2
CO Me
PhCF3, rt, N2
R
TBS
6
5
8
R =
tBu
ba', 73%, 97 : 3 er 8ea', 56%, 93 : 7 er 8da', 83%, 92 : 8 er
8
8ta', 19%, 89 : 11
MeO
Br
I
F3C
8ga', 77%, 93 : 7 er 8ra', 63%, 93 : 7 er 8qa', 81%, 95 : 5 er 8ka', 70%, 89 : 11 er
N
NC
TfO
O2N
Tf
8va', 75%, 87 : 13 er 8ja', 45%, 94 : 6 er 8ha', 77%, 93 : 7 er 8la', 62%, 91 : 9 er
The further investigation was focused on the alkene reduction and the cyclization to produce the desired
pyrrolizinones. Main concerns while developing the two-step procedure were the preservation of the C3
stereogenic center, the control of diastereoselectivity at C2 and the operational simplicity of the sequence.
Attempts to carry out cyclization followed by reduction failed due to the lability of Michael acceptor under
acidic conditions. This prompted exploration of the reverse sequence: reduction followed by cyclization.
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Scheme 4. Hydrogenation of N-allyl pyrroles 8. Isolated yields for the inseparable mixtures of anti and syn
1
diastereomers and the diastereomeric ratio determined by H NMR are shown. Relative stereochemistry is
1
tentatively assigned based on H NMR and the results of cyclization experiments. Reactions were
performed with both racemic material and enantioenriched material (for 8ba and 8ea). Conditions: 10 mol%
0
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Pd/C, 1 atm. H
, MeOH. [a]Isolated yields of anti-9sa and syn-9sa which do not account for losses of each
2
isomer during purification
N
O
N
O
N
O
Pd/C, H2 (1 atm)
MeOH
R
OMe
R
OMe
R
OMe
8
anti-9
syn-9
R =
Ph
Ph
MeO
9
ba, >99%
9ea, 99%
dr 3.5 : 1
9ua, 81%
dr 2.4 : 1
9ta, 96%
dr 1.3 : 1
9fa, 87%
dr 2.6 : 1
dr 1.4 : 1
F
F3C
MeO2C
NC
anti-9sa, 20%[a]
syn-9sa, 40%[a]
9na, 81%
dr 3.1 : 1
9ka, 75%
dr 3 : 1
9ia, 86%
dr 1.7 : 1
9ja, 97%
dr 1.6 : 1
With a large pool of methods for 1,4-reduction to choose from,14 we opted for the simplest heterogeneous
hydrogenation of 8 over palladium catalyst which provided the desired reduction product in excellent yield
but with low diastereoselectivity (Scheme 4). This was not seen as a setback as it allowed access to both
diastereomers of the reduced products which were of interest in subsequent cyclization attempts. The
difficulties in separating the two diastereomers, however, brought about the search for a substrate that
would allow the easier separation of the two isomers. All attempted reductions proceeded with good yields
4
and low diastereoselectivities ranging from 1.3:1 to 3.5:1 without an obvious trend (Scheme 4). It was only
the syn- and anti-isomers of naphthyl substituted ester 9sa that could be separated by column
chromatography.
Having access to both syn- and anti-diastereomers of 9sa, the conditions for cyclization reactions became
a focal point. In the presence of a pyrrole and an aryl substituent at the C3, Friedel-Crafts-type cyclization
was a logical choice for cyclization as we expected the electron rich pyrrole to outperform the aryl
substituent. On the other hand, mild reaction conditions were desired in order to minimize the epimerization
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i
4 3
at C2. To reconcile these requirements, numerous Lewis and Brønsted acids (AlCl3, Ti(OPr) , BF , TMSOTf
andTfOH among others) were tested as potential promotors of the cyclization to no avail. Only the treatment
afforded the desired cyclization product, albeit in moderate yield.15 This suggested the in-situ
with BBr
3
formation of an acyl bromide which further reacts to form the pyrrolizinone (see Scheme 5). To test this, the
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ester was hydrolyzed, and the corresponding acid was treated with PBr
3
to form the cyclization product
although in lower yields.
Scheme 5. a) Evaluation of the diastereoselectivity for cyclizations of anti-9sa and syn-9sa and plausible
mechanism for the isomerization. b) Proposed mechanism for cyclization and isomerization of 9.
a)
N
O
N
N
N
O
BBr3
BBr3
O +
NAP
O
NAP
OMe
NAP
NAP
OMe
CH2Cl2
CH2Cl2
trans-7sa
major
cis-7sa
minor (traces)
anti-9sa
syn-9sa
b)
Lewis
acid
Lewis
acid
BBr3
OMe
N
O
N
O
N
N
O
OH
R
R
Br
R
R
Independent cyclization of syn-9sa and anti-9sa, somewhat surprisingly, afforded the same isomer of 7sa
as the major cyclization product tentatively assigned as trans-7sa based on the 3JH-H coupling constants for
C2 and C3 protons. When these reactions were stopped at ~50% conversion, the re-isolated starting
2
material was unchanged suggesting that isomerization happens upon cyclization. With three sp atoms in
the pyrrolidinone ring, we expected the low energy conformations to be rather flat which would cause
significant gauche interactions between C2 and C3 substituents in the cis isomer of 7 making the trans
isomer increasingly more stable than the cis as the substituents become larger (like in the case of naphthyl
derivative 7sa).
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
Scheme 6. Diastereoselective cyclization of mixtures of anti-9 and syn-9 to pyrrolizinones 7. Isolated yields
for the major diastereomer and the diastereomeric ratio are shown. Conditions: 1.05 equiv. BBr
(0.1 M)
3 2 2
, CH Cl
N
O
N
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
BBr3, CH2Cl2
+
O
O
R
OMe
R
R
9
trans-7
cis-7
N
N
N
N
O
O
O
O
Ph
Ph
trans-7ba, 53%
dr 5 : 1, er 97 : 3
trans-7ea, 53%
dr 19 : 1, er 93 : 7
trans-7ua, 55%
dr > 25 : 1
trans-7ta, 62%
dr > 25 : 1
N
N
N
O
O
O
MeO
F
trans-7fa, 32%
trans-7sa, 24%
trans-7na, 53%
dr > 25 : 1
dr > 25 : 1
dr 8 :1
N
N
N
O
O
O
F3C
NC
MeO2C
trans-7ka, 30%
dr > 25 : 1
trans-7ia, 22%
trans-7ja, 46%
dr 24 : 1
dr 7 : 1
Since the configuration of 9 does not appear to significantly influence the diastereoselectivity in the
cyclization to form cis- and trans-7 (although it may influence the reaction rates and overall yield), we carried
out BBr
3
promoted cyclization using mixtures of diastereomers for a series of N-allyl pyrroles 9 (Scheme
6
5
). The desired pyrrolizinones (Scheme 6) were isolated with good to excellent diastereoselectivity between
:1 and >25:1. The diastereomers could be separated in each case with trans-isomer being the major
1
product in all attempted cyclizations. Assignment of the cis and trans isomers was made based on H NMR
spectra and the 3JH-H coupling constants for C2 and C3 protons which were consistent across the series
with values of around 4.8 Hz for the trans-7 and around 7.7 Hz for cis-7, the latter being indicative of the
close to syn-periplanar arrangement of these protons in cis-7. The isolated yields for the major
diastereomers range from 22% to 62% (Scheme 6). These moderate yields are likely a consequence of the
rather harsh reaction conditions and the side reactions which include competitive degradation of ether,
ester, trifluoromethyl and nitrile substituents (7fa, 7ka, 7ia and 7ja),16 and intramolecular electrophilic
aromatic substitution on the C3-aryl substituent. The substrates with alkyl substituents, and therefore with
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no opportunity for the competing Friedel-Crafts involving the C3 substituent, performed much better in the
cyclization reactions to produce 7ua and 7ta. Finally, when enantioenriched N-allyl pyrroles 8 were used in
the two-step sequence, the yields and diastereoselectivity in both hydrogenation and cyclization reactions
remained unaffected. Same is true for the configuration at C3 and therefore the enantiomeric ratios of the
trans-7 products. Products trans-7ba and trans-7ea, for example, were isolated with enantiomeric ratios of
1
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1
1
1
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2
2
2
2
2
2
2
2
2
2
3
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5
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5
6
0
1
2
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4
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8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
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7
8
9
0
1
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7
8
9
0
1
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4
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7
8
9
0
97:3 and 93:7, respectively, which matches that of the of starting materials 8ba’ and 8ea’.
In conclusion, the three-step sequence of pyrrole N-allylation followed by simple Pd-catalyzed
hydrogenation and BBr promoted cyclization is an effective route for the synthesis of substituted 2,3-
3
dihydro-1H-pyrrolizin-1-ones. The concept of latent nucleophiles in Lewis base catalysis is a powerful tool
for the development of enantioselective allylic substitutions with the broad scope for both reaction partners.
The use of N-TBS pyrrole as a latent nucleophile in combination with allylic fluorides and common chiral
Lewis base catalysts allows for the enantioselective N-allylation of pyrrole and, for the first time, enables
the synthesis of enantioenriched pyrrolizin-1-ones via the said three step sequence. These enantioenriched
materials are required for further biological evaluation of their radical scavenging and anti-amyloid
properties which will be reported in due course.
Experimental section
General remarks. All the chemicals that are not mentioned in the subsequent parts were purchased from Merck, Alfa
Aesar, Acros Organics, ABCR, Fluorochem or TCI and used without further purification. The solvents if needed were
dried according to standard laboratory practices. For column chromatography and TLC (SiO
.063 mm), products of Machery-Nagel were used. The TLC-glass-plates DURASIL consisted of a 0.25 mm layer of
silica 60 with Fluorescence indicator UV254. TLCs were checked under UV-light (254 nm or 365 nm) and stained with
an aq. KMnO -solution, PMA-stain, DNP or PAA solution. Reaction monitoring using GC-MS was performed using HP
2
, 60M, pore size 0.04 –
0
4
6890, capillary column DB5-MS and Agilent 5973 MSD. The default method was 70 °C (2 min), ramp 20 °C/min to 270
1
°
C, hold 10 min. Injector temperature 250 °C, Aux temperature 275 °C. All H, 13C and 19F NMR spectra were measured
with a BRUKER 250 ( C), BRUKER Fourier 300 ( H, C) or a BRUKER Avance 400 spectrometer ( H, 13C, 19F). The
1
3
1
13
1
chemical shift of each signal was registered in ppm. For H and 13C measurements, the chemical shift refers to TMS,
1
showing a signal at 0 ppm. As an internal standard, the remaining protons or respectively the carbons of the
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1
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6
1
13
3
corresponding deuterated solvent were used (CDCl , 7.26 ppm ( H-NMR), 77.16 ppm ( C-NMR)). The chemical shift
of the fluorine NMR was determined indirectly. For carbon spectra, a broadband decoupling was performed.
Enantiomeric excess was determined by HPLC analysis on Phenomenex Lux Cellulose-1 columns. High-resolution
mass spectra (HRMS) were measured with EI or ESI ionization by the MS platform. A chromatographic purification was
performed before each measurement. The Thermo Q-Exactive plus device for ESI-mass spectra was coupled to a
binary UHPLC system using orbitrap as mass analyzer. For EI-measurement, a GC-system was coupled to the Thermo
Q-Exactive (quadrupole) GC Orbitrap device. All the IRs were measured using the Shimadzu IR-Affinity-1 (FTIR)
device.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
Synthesis of Morita Baylis Hillman (MBH) Fluorides 5. DAST (1.1 or 1.2 equiv.) was added to CH
this, a precooled solution of MBH adduct (1 equiv.) in CH Cl was added slowly (overall concentration MBH 0.25 M in
CH Cl ). The mixture was stirred for 30 minutes and then quenched with sat. NaHCO solution. The mixture was
extracted twice with CH Cl . The combined organic layers were dried over Na SO and concentrated under reduced
2 2
Cl at -78 °C. To
2
2
2
2
3
2
2
2
4
pressure. The crude product was purified by flash column chromatography using either ethyl acetate in petroleum ether
or ether in petroleum ether. The data for the known compounds 5a, 5b, 5c, 5g, 5k, 5l, 5m, 5n, 5o, 5p, 5q, 5s, 5t, 5v13
7
and 5d, 5e, 5f, 5h, 5i, 5j and 5u are consistent with previous reports.
methyl 2-((4-iodophenyl)fluoromethyl)acrylate (5r). 4-iodo-benzaldehyde (2.00 g, 8.60 mmol mmol) was treated
with DABCO (0.48 g, 4.30 mmol) in methyl acrylate (1.48 g, 17.2 mmol) and stirred at ambient temperature till judged
completed by TLC. The crude mixture was directly subjected to column chromatography (silica) using ethyl acetate and
petroleum ether (15:85) as solvent system to give the corresponding alcohol, methyl 2-(hydroxy(4-iodo)methyl)acrylate
1
as a colorless solid. Yield: 1.34 g, 4.21 mmol, 49%. H-NMR (400 MHz, CDCl
3
) δ 7.71 – 7.67 (d, J = 8.8 Hz, 2H), 7.19
–
7.10 (d, J = 8.8 Hz, 2H), 6.36 (s, 1H), 5.85 (s, 1 H), 5.51 (d, J = 4.5 Hz, 1H), 3.75 (s, 3H), 3.16 (s. 1H). 13C{1H}-NMR
63 MHz, CDCl ) δ 167.5, 142.4, 141.9, 138.4, 129.4, 127.4, 94.4, 73.8, 53.0. HRMS [EI]: m/z calculated for C11
M] 317.9747; found 317.9746. IR (ATR): 휈 = 3441 (br, w), 1709, (vs), 1420 (m), 1146 (vs), 1138 (s), 1007 (vs) cm .
(
3
H11IO
3
+
-1
[
The corresponding MBH fluoride was prepared by general procedure for synthesis of Morita Baylis Hillman fluorides.
1
) δ 7.74 (d, J = 7.8 Hz, 2H), 7.16 (d, 3JH,H
Yield: colorless solid, 434 mg, 1.36 mmol, 44%. H-NMR (400 MHz, CDCl
3
=
9
.4 Hz, 2H), 6.48 (d, J = 2.8 Hz, 1H ), 6.24 (d, J = 45.8 Hz, 1H), 6.05 (s, 1H), 3.74 (s, 3H). 13C{1H}-NMR (101 MHz,
3
CDCl ) δ 165.0 (d, J = 6.4 Hz), 138.9 (d, J = 22.9 Hz), 137.7, 137.1 (d, J = 20.8 Hz), 128.9 (d, i = 5.6 Hz), 126.2 (d, J =
19
8
3
.8 Hz), 90.2 (d, J = 174.9 Hz), 52.1 . F-NMR (377 MHz, CDCl ) δ -172.54 (d, J = 45.8 Hz). HRMS [EI]: m/z calculated
+
for C11
H
10FIO
2
[M] 319.9704, found 319.9702. IR (ATR): 휈 = 2959(w), 1713 (s), 1273 (s) 1165 (m), 964 (s), 806 (s)
-1
cm .
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Synthesis of N-silyl-N-heterocycles 6. Under nitrogen atmosphere, the heterocycle (1 equiv.) was dissolved in THF
cooled to -78°C and then n-BuLi (1.1 equiv.) or NaH (1.1 equiv) was added and stirred at this temperature for 15
minutes. TBS-chloride (1.2 equiv.) was added portion-wise. The reaction mixture was allowed to warm to room
temperature. The reaction was quenched with water and then extracted with diethyl ether. The combined organic layers
1
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1
1
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1
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2
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2
2
2
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2
2
2
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5
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5
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0
1
2
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
were dried over Na
2 4
SO and the solvent was removed under reduced pressure. The crude mixtures were either distilled
or subjected to column chromatography using ethyl acetate in petroleum ether. The analytical data for known
7
19
compounds 6b, 6c, 6h, 6l, 6f, 6k, and 6j matched the previously reported data. Compounds 6a, 6d (TIPS derivative),
e (TIPC derivative), 6g and 6i are commercially available.
Substitution of Allylic fluorides. The TBS protected pyrrole, indole or carbazole 6 (for 6a: 1.04 g, 5.67 mmol) and
DABCO (28.9 mg, 0.26 mmol) were dissolved in CH Cl (15 mL). To this, a solution of allylic fluoride (for 5b: 1.00 g,
.15 mmol) in CH Cl (15 mL) was added slowly. After the completion of the reaction (monitored by TLC), the mixture
6
2
2
5
2
2
was concentrated and purified by flash column chromatography using ethyl acetate in petroleum ether.
benzyl 2-((1H-pyrrol-1-yl)methyl)acrylate (8aa). Yield: colorless oil, 23.8 mg, 0.100 mmol, 83%. Chromatography:
1
ethyl acetate: petroleum ether 10:90. H-NMR (250 MHz, CDCl
3
) δ 7.41 (s, 5H), 6.69 (t, J = 2.1 Hz, 2H), 6.36 (d, J =
1
.1 Hz, 1H), 6.22 (t, J = 2.1 Hz, 2H), 5.35 (d, J = 0.9 Hz, 1H), 5.26 (s, 2H), 4.80 (s, 2H). 13C{1H}-NMR (63 MHz, CDCl3)
δ 166.2, 138.8, 136.5, 129.5, 129.3, 129.1, 127.5, 122.1, 109.5, 67.7, 50.9. HRMS [ESI]: m/z calculated for C15
H
15NO
2
+
-1
[
M] 241.1097, found 241.1097. IR (ATR): 휈 = 2924 (w), 1713 (s), 1288 (m), 1134 (m), 1088 (m), 725 (s) cm .
methyl 2-(phenyl(1H-pyrrol-1-yl)methyl)acrylate (8ba).7 Yield: colorless solid, 1.09 g, 5.15 mmol, 88%.
Chromatography: ethyl acetate: petroleum ether 5:95.
methyl 2-((1H-pyrrol-1-yl)(p-tolyl)methyl)acrylate (8ca). Yield: colorless oil, 65.2 mg, 0.255 mmol, 83%.
1
Chromatography: ethyl acetate: petroleum ether 5:95. H-NMR (400 MHz, CDCl
3
) δ 7.07 (d, J = 7.9 Hz, 2H), 6.99 (d, J
=
0
8.2 Hz, 2H), 6.51 (t, J = 2.1 Hz, 2H), 6.37 (d, J = 1.0 Hz, 1H), 6.23 (s, 1H), 6.07 (t, J = 2.2 Hz, 2H), 5.13 (dd, J = 1.6,
.8 Hz, 1H), 3.63 (s, 3H), 2.26 (s, 3H). 13C{1H}-NMR (101 MHz, CDCl
) δ 166.1, 141.2, 138.0, 135.1, 129.4, 127.9,
3
+
127.5, 120.7, 108.3, 62.6, 52.2, 21.1. HRMS [ESI]: m/z calculated for C16
H
17NO
2
[M] 255.1254, found 255.1255. IR
-1
(
ATR): 휈 = 2951 (w), 1721 (vs), 1435 (m), 1273 (s), 1138 (vs), 721 (vs) cm .
7
methyl 2-((4-(tert-butyl)phenyl)(1H-pyrrol-1-yl)methyl)acrylate (8da). Yield: colorless oil, 63.3 mg, 0.210 mmol,
7
9%. Chromatography: ethyl acetate: petroleum ether 7.5:92.5.
methyl 2-((3,5-dimethylphenyl)(1H-pyrrol-1-yl)methyl)acrylate (8ea).7 Yield: colorless oil, 77.0 mg, 0.29 mmol,
8
4%. Chromatography: diethyl ether : petroleum ether 5:95
7
methyl 2-((4-methoxyphenyl)(1H-pyrrol-1-yl)methyl)acrylate (8fa). Yield: colorless solid, 35.7 mg, 0.130 mmol,
77%. Chromatography: ethyl acetate: petroleum ether 10:90
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methyl 2-((3-methoxyphenyl)(1H-pyrrol-1-yl)methyl)acrylate (8ga). Yield: colorless oil, 49.0 mg, 0.18 mmol, 84%.
Chromatography: ethyl acetate: petroleum ether 10:90
methyl 2-((1H-pyrrol-1-yl)(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)methyl)acrylate (8ha).7 Yield: colorless oil,
6
5.5 mg, 0.17 mmol, 80%. Chromatography: ethyl acetate: petroleum ether 20:80
methyl 4-(2-(methoxycarbonyl)-1-(1H-pyrrol-1-yl)allyl)benzoate (8ia). 7 Yield: colorless solid, 88.2 mg, 0.29 mmol,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
92%. Chromatography: ethyl acetate: petroleum ether 15:85.
methyl 2-((4-cyanophenyl)(1H-pyrrol-1-yl)methyl)acrylate (8ja). Yield: colorless oil, 41.0 mg, 0.15 mmol, 92%.
Chromatography: ethyl acetate: petroleum ether 10:90 1H-NMR (250 MHz, CDCl
3
) δ 7.73 – 7.60 (d, J =8.3 Hz, 2H),
7.28 (d, J = 8.2 Hz, 2H), 6.61 (t, J = 2.1 Hz, 1H), 6.57 (s, 1H), 6.42 (s, 1H), 6.23 (t, J = 2.2 Hz) 5.30 (s, 1H), 3.77 (s,
3
H). 13C{1H}-NMR (63 MHz, CDCl
3
) δ 166.5, 144.8, 140.8, 133.5, 130.0, 129.4, 121.5, 119.3, 113.1, 110.1, 63.1, 53.4.
+
HRMS [EI]: m/z calculated for C16
H
14
N
2
O
2
[M] 266.1050, found 266.1052. IR (ATR): 휈 = 2955 (w), 2230 (w), 1721 (s),
273 (m), 1142 (s), 725 (vs) cm-1.
1
methyl 2-((4-(trifluormethyl)-phenyl)(1H-pyrrol-1-yl)methyl)acrylate (8ka).7 Yield: colorless solid, 60.5 mg,
.20 mmol, 82%. %. Chromatography: ethyl acetate: petroleum ether 10:90
0
methyl 2-((4-nitrophenyl)(1H-pyrrol-1-yl)methyl)acrylate (8la).7 Yield: colorless oil, 30.6 mg, 0.11 mmol, 79%.
Chromatography: diethyl ether : petroleum ether 30:70
methyl 4-((3-nitrophenyl)(1H-pyrrol-1-yl)allyl)benzoate (8ma). Yield: colorless oil, 30.0 mg, 0.10 mmol, 71%.
1
Chromatography: ethyl acetate: petroleum ether 10:90 H-NMR (250 MHz, CDCl
3
) δ 8.22 (dd, J = 8.0, 1.9 Hz, 1H),
8
.06 (d, J = 2.0 Hz, 1H), 7.68 – 7.39 (m, 2H), 6.62 (dd, J = 5.0, 2.7 Hz, 3H), 6.47 (s, 1H), 6.24 (d, J = 2.1 Hz, 2H), 5.33
(s, 1H), 3.77 (d, J = 1.6 Hz, 3H). 13C{1H}-NMR (63 MHz, CDCl
) δ 166.4, 149.5, 141.6, 140.8, 134.8, 130.8, 123.0,
3
+
1
24.2, 123.7, 121.5, 110.2, 62.9, 53.4. HRMS [ESI]: m/z calculated for C15
H
14
N
2
O
4
[M] 286.0954, found 286.0948. IR
-1
(
ATR): 휈 = 2955 (w), 1721 (s), 1528 (vs), 1346 (vs), 1273 (s), 725 (vs) cm .
methyl 2-((4-fluorophenyl)(1H-pyrrol-1-yl)methyl)acrylate (8na). Yield: colorless solid, 62.1 mg, 0.24 mmol, 68%.
1
Chromatography: ethyl acetate: petroleum ether 10:90. H-NMR (400 MHz, CDCl
3
) δ 7.18 (dd, J = 8.6, 5.3 Hz, 2H),
7
.07 (t, J = 8.6 Hz, 2H), 6.61 (t, J = 2.1 Hz, 2H), 6.50 (s, 1H), 6.36 (s, 1H), 6.20 (t, J = 2.1 Hz, 2H), 5.25 (d, J = 2.0 Hz,
H), 3.75 (s, 3H). 13C{1H}- NMR (101 MHz, ) δ 165.9 , 162.5 (d, JC-F = 247.2 Hz), 141.0 , 134.0 (d, JC-F = 3.3 Hz), 129.7
1
(
d, JC-F = 8.2 Hz), 127.9, 120.6, 115.7 (d, JC-F = 21.7 Hz), 108.6, 62.1, 52.3. 19F-NMR (377 MHz, CDCl
3
) δ -113.82.
+
HRMS [ESI]: m/z calculated for C15
H
14FNO
2
[M] 259.1003, found 259.1007. IR (ATR): 휈 = 2951 (w), 1717 (s), 1508
-1
(
s), 1265 (m), 1219 (m) 1134 (m), 733 (vs) cm .
7
methyl 2-((4-chlorophenyl)(1H-pyrrol-1-yl)methyl)acrylate (8oa). Yield: colorless oil, 40.0 mg, 0.14 mmol, >99%.
Chromatography: ethyl acetate: petroleum ether 15:85.
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methyl 2-((4-bromophenyl)(1H-pyrrol-1-yl)methyl)acrylate (8pa). Yield: colorless solid, 61.7 mg, 0.19 mmol, 84%.
1
Chromatography: ethyl acetate: petroleum ether 10:90 H-NMR (250 MHz, CDCl
3
) δ 7.48 (d, J = 8.4 Hz, 2H), 7.03 (d,
J = 8.4 Hz, 2H), 6.58 (t, J = 2.2 Hz, 2H), 6.49 (s, 1H), 6.30 (s, 1H), 6.17 (t, J = 2.2 Hz, 2H), 5.23 (s, 1H), 3.72 (s, 3H).
13C{1H}-NMR (63 MHz, CDCl
3
) δ 166.7, 141.5, 138.3, 132.8, 130.5, 129.1, 123.2, 121.5, 109.6, 63.1, 53.2. HRMS [EI]:
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H14NO
2
BrNa [M+Na] 342.0106, found 342.0106. IR (ATR): 휈 = 2951 (w), 1721 (vs), 1489 (m),
+
m/z calculated for C15
-1
1
273 (s), 1142 (s), 1072 (m), 725 (vs) cm .
methyl 2-((3-bromophenyl)(1H-pyrrol-1-yl)methyl)acrylate (8qa).7 Yield: colorless oil, 58.0 mg, 0.18 mmol, 82%.
Chromatography: ethyl acetate: petroleum ether 10:90.
methyl 2-((4-iodophenyl)(1H-pyrrol-1-yl)methyl)acrylate (8ra). Yield: colorless solid, 69.0 mg, 0.19 mmol, 82%.
1
Chromatography: diethyl ether : petroleum ether 10:90 H-NMR (300 MHz, CDCl
3
) δ 7.77 – 7.50 (m, 2H), 6.96 – 6.80
(m, 2H), 6.57 (t, J = 2.1 Hz, 2H), 6.48 (t, J = 0.8 Hz, 1H), 6.29 (s, 1H), 6.17 (t, J = 2.2 Hz, 2H), 5.24 (d, J = 1.5 Hz, 1H),
3
.72 (s, 3H). 13C{1H}-NMR (75 MHz, CDCl
3
) δ 165.8, 140.6, 138.1, 137.9, 129.9, 128.3, 120.7, 108.8, 94.1, 62.3, 52.4.
+
HRMS [ESI]: m/z calculated for C15
H
14INO
2
[M] 367.0064, found 367.0066. IR (ATR): 휈 = 2947 (w), 1697 (vs), 1481
-1
(
m), 1439 (m), 1269 (m), 1142 (s), 1084 (s), 737 (vs) cm .
methyl 2-(naphthalen-2-yl(1H-pyrrol-1-yl)methyl)acrylate (8sa).7 Yield: yellow solid, 61.4 mg, 0.21 mmol, 88%.
Chromatography: ethyl acetate: petroleum ether 10:90.
methyl 2-(cyclohexyl(1H-pyrrol-1-yl)methyl)acrylate (8ta).7 Yield: colorless oil, 26.5 mg, 0.11 mmol, 84%.
Chromatography: diethy lether: petroleum ether 5:95.
7
methyl 2-methylene-5-phenyl-3-(1H-pyrrol-1-yl)pentanoate (8ua). Yield: colorless oil, 45.5 mg, 0.169 mmol, 55%.
Chromatography: ethyl acetate: petroleum ether 2.5:97.5.
7
methyl 2-((1H-pyrrol-1-yl)(1-((trifluoromethyl)sulfonyl)-1H-indol-3-yl)methyl)acrylate (8va). Yield: colorless wax,
38.3 mg, 0.09 mmol, 71%. Chromatography: diethyl ether: petroleum ether 5:95.
7
methyl 2-((2-cyano-1H-pyrrol-1-yl)(phenyl)methyl)acrylate (8bb). Yield: colorless oil, 26.6 mg, 0.100 mmol, 67%.
Chromatography: ethyl acetate: petroleum ether 10:90.
7
methyl 1-(2-(methoxycarbonyl)-1-phenylallyl)-1H-pyrrole-2-carboxylate (8bc). Yield: brown oil, 37.5 mg, 0.125
mmol, 67%. Chromatography: ethyl acetate: petroleum ether 10:90.
methyl 2-((1H-indol-1-yl)(phenyl)methyl)acrylate (8bf).12c Yield: colorless solid, 86.2 mg, 0.285 mmol, 96%.
Chromatography: ethyl acetate: petroleum ether 10:90.
methyl 2-((5-nitro-1H-indol-1-yl)(phenyl)methyl)acrylate (8bg).7 Yield: brown solid, 49.3 mg, 0.147mmol, 77%.
Chromatography: ethyl acetate: petroleum ether 15:85.
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methyl 2-((4-cyano-1H-indol-1-yl)(phenyl)methyl)acrylate (8bh). 7 Yield: colorless oil, 7.8 mg, 0.025 mmol, 93%.
Chromatography: ethyl acetate: petroleum ether 15:85.
methyl 2-((5-bromo-1H-indol-1-yl)(phenyl)methyl)acrylate (8bi).12c Yield: colorless oil, 60.7 mg, 0.163 mmol, 90%.
Chromatography: ethyl acetate: petroleum ether 15:85.
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methyl 2-((5-methoxy-1H-indol-1-yl)(phenyl)methyl)acrylate (8bj). Yield: colorless solid, 74.0 mg, 0.22 mmol, 88%.
Chromatography: ethyl acetate: petroleum ether 15:85.
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methyl 2-((2-methyl-1H-indol-1-yl)(phenyl)methyl)acrylate (8bk). Yield: colorless oil, 37.6 mg, 0.123 mmol, 47%.
Chromatography: ethyl acetate: petroleum ether 5:95.
methyl 2-((9H-carbazol-9-yl)(phenyl)methyl)acrylate (8bl).7 Yield: colorless solid, 52.4 mg, 0.15 mmol, 82%.
Chromatography: ethyl acetate: petroleum ether 10:90.
benzyl 2-((5-bromo-1H-indol-1-yl)methyl)acrylate (8ai). Yield: colorless solid, 23.7 mg, 0.064 mmol, 89%.
1
Chromatography: ethyl acetate: petroleum ether 10:90 H-NMR (400 MHz, CDCl
3
) δ 7.78 (d, J = 1.8 Hz, 1H), 7.39 (dd,
J = 5.0, 3.3 Hz, 5H), 7.32 – 7.25 (m, 1H), 7.20 – 7.09 (m, 2H), 6.54 – 6.46 (m, 1H), 6.33 (s, 1H), 5.25 (s, 2H), 5.21 (s,
1
1
3
H), 5.01 (s, 2H). 13C{1H}-NMR (101 MHz, CDCl
3
) δ 165.2, 136.1, 135.4, 134.7, 130.3, 129.5, 128.7, 128.5, 128.3,
+
26.7, 124.7, 123.5, 113.0, 111.1, 101.6, 67.0, 47.0. HRMS [EI]: m/z calculated for C19
H
16NO
2
Br [M] 369.0365, found
69.0364. IR (ATR): 휈 = 2928 (w), 1721 (s), 1466 (m), 1258 (vs), 1157 (vs), 736 (vs) cm-1.
benzyl 2-((1H-indol-1-yl)methyl)acrylate (8af). Yield: colorless oil, 24.4 mg, 0.084 mmol, 69%. Chromatography:
ethyl acetate: petroleum ether 10:90 1H-NMR (400 MHz, CDCl
3
) δ 7.77 – 7.67 (m, 1H), 7.41 (d, J = 3.4 Hz, 5H), 7.35
–
7.12 (m, 4H), 6.61 – 6.53 (m, 1H), 6.33 (s, 1H), 5.28 (s, 2H), 5.22 (s, 1H), 5.06 (s, 2H). 13C{1H}-NMR (101 MHz,
CDCl
3
) δ 165.4, 136.4, 136.0, 135.6, 128.7, 128.6, 128.5, 128.4, 128.3, 126.6, 121.8, 121.0, 119.7, 109.6, 102.0, 66.9,
+
46.8. HRMS [ESI]: m/z calculated for C19
H
17NO
2
[M] 291.1259, found 291.1253. IR (ATR): 휈 = 2951 (w), 1712 (s),
-1
1
462 (m), 1258 (vs), 1130 (s), 737 (vs) cm .
benzyl 2-((2-methyl-1H-indol-1-yl)methyl)acrylate (8ak). Yield: colorless oil, 20.0 mg, 0.070 mmol, 69%.
Chromatography: ethyl acetate: petroleum ether 10:90 1H-NMR (250 MHz, CDCl
3
) δ 7.63 – 7.56 (m, 1H), 7.50 – 7.40
(m, 5H), 7.25 – 7.04 (m, 3H), 6.40 – 6.32 (m, 1H), 6.26 (s, 1H), 5.33 (s, 2H), 5.00 (t, J = 2.0 Hz, 2H), 4.87 (d, J = 2.1
Hz, 1H), 2.40 (s, 3H).). 13C{1H}-NMR (101 MHz, CDCl
) δ 165.5, 136.7, 136.4, 136.1, 135.6, 128.7, 128.5, 128.3, 128.2,
3
+
1
2
25.6, 120.9, 119.8, 119.7, 109.0, 100.7, 66.9, 43.3, 12.4. HRMS [ESI]: m/z calculated for C20H19NO [M] 305.1416,
-1
found 305.1416. IR (ATR): 휈 = 1708 (s), 1454 (m), 1369 (m), 1292 (vs), 1130 (s), 737 (vs) cm .
methyl 1-(2-(methoxycarbonyl)-1-(4-(trifluoromethyl)phenyl)allyl)-1H-pyrrole-2-carboxylate (8kc).7 Yield:
colorless oil, 26.6 mg, 0.072 mmol, 72%. Chromatography: diethyl ether: petroleum ether 20:80.
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methyl 4-(1-(1H-indol-1-yl)-2-(methoxycarbonyl)allyl)benzoate (8if). Yield: colorless solid, 74.0 mg, 0.22 mmol,
8%. Chromatography: ethyl acetate: petroleum ether 20:80.
methyl 2-((5-bromo-1H-indol-1-yl)(2-fluorophenyl)methyl)acrylate (8wi). Yield: colorless oil, 30.5 mg, 0.08 mmol,
4%. Chromatography: diethyl ether: petroleum ether 10:90.
8
7
4
7
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6
7
8
9
0
methyl 2-((9H-carbazol-9-yl)(4-cyanophenyl)methyl)acrylate (8jl). Yield: colorless solid, 81.2 mg, 0.22 mmol, 82%.
Chromatography: ethyl acetate: petroleum ether 15:85.
7
methyl 2-((4-chlorophenyl)(3-cyano-1H-indol-1-yl)methyl)acrylate (8om). Yield: wax, 65.0 mg, 0.19 mmol, 77%.
Chromatography: ethyl acetate: petroleum ether 15:85
7
methyl 2-((5-bromo-1H-indol-1-yl)(2-bromophenyl)methyl)acrylate (8xi). Yield: colorless oil, 58.0 mg, 0.13 mmol,
8
4%. Chromatography: diethyl ether: petroleum ether 10:90
General procedure for enantioselective allylation of N-heterocycles. To a flask with N-silyl heterocycle (0.1 mmol)
and (DHQD) PHAL (7.8 mg, 10 mol %) were added successively and the flask was then evacuated and refilled with
nitrogen. This procedure was repeated three times. Dry PhCF (0.5 mL), dissolving MBH fluorides (0.2 mmol) was then
added. The reaction mixture was stirred at room temperature. After stirring for 40 h or the completion of the reaction
monitored by TLC), the mixture was concentrated and purified by flash column chromatography with ethyl acetate in
2
3
(
petroleum ether to afford the corresponding product. NMR Data was compared with the racemic material. The ratio of
enantiomers was determined by HPLC on chiral stationary phase.
General procedure Hydrogenation of Substitution products. The substrate (1.equiv.) was dissolved in MeOH (1mL)
and degassed with nitrogen for 5 minutes. Pd/C (10 mol%) was added and hydrogen was bubbled through the mixture
until observed to be completed (by GC-MS). The reaction mixture was filtered on a plug of silica eluting with ethyl
acetate if not stated differently.
methyl 2-methyl-3-phenyl-3-(1H-pyrrol-1-yl)propanoate (9ba). Yield: colorless solid, 166 mg, 0.68 mmol, >99%.
1
Mixture of diastereomers. H NMR (250 MHz, CDCl
3
) δ 7.45 – 7.22 (m, 5H), 6.79 (m, 2H), 6.22 – 6.08 (m, 2H), 5.21
13
(
3
m, 1H), 3.62 (s, 3H (major)), 3.62 (s, 3H (minor)) 3.55 – 3.40 (m, 1H), 1.16 (m, 3H). C{1H} NMR (63 MHz, CDCl ) δ
1
4
75.7, 175.4, 140.3, 139.5, 129.8, 129.6, 129.1, 129.0, 128.3, 127.9, 120.6, 120.3, 109.4, 109.2, 67.2, 66.6, 53.0, 52.8,
+
6.0, 45.8, 16.9, 165. HRMS [ESI]: m/z calculated for C15
H
17NNaO
2
[M+Na] 266.1157, found 266.1161. IR (ATR): ν=
-1
2935 (w), 1728 (vs), 1454 (m), 1261 (m), 1092 (m), 725 (vs); 702 (vs) cm .
methyl
3-(3,5-dimethylphenyl)-2-methyl-3-(1H-pyrrol-1-yl)propanoate
(9ea).
Yield:
colorless
solid,
1
2
4.3 mg, 0.09 mmol, >99%. Mixture of diastereomers. H NMR (400 MHz, CDCl
3
) δ 6.96 (m, 3H), 6.78 (m, 2H), 6.17
(
m, 2H (minor)), 6.11 (m, 2H (major)), 5.12 (m, 1H), 3.59 (s, 3H, (major)), 3.52 – 3.40 (s, 3H (minor)), 2.31 (m, 6H),
13
3
1.13 (m, 3H). C{1H} NMR (101 MHz, CDCl ) δ 175.0, 174.5, 139.2, 138.38, 138.37, 138.1, 129.9, 129.8, 125.2, 124.8,
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19.7, 119.4, 108.4, 108.1, 66.4, 65.6, 52.0, 51.8, 45.0, 44.9, 21.4, 16.1, 15.6, 15.5. HRMS [ESI]: m/z calculated for
+
C
17
H
21NO
2
[M] 271.1567, found 271.1570. IR (ATR): ν= 3951 (w), 1753 (vs), 1458 (m), 1265(m), 1165 (m), 718 (vs),
-1
698 (s) cm .
methyl 2-methyl-5-phenyl-3-(1H-pyrrol-1-yl)pentanoate (9ua). Yield: colorless oil, 22 mg, 0.08 mmol. Mixture of
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
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5
6
7
8
9
0
1
3
diastereomers. H NMR (400 MHz, CDCl ) δ 7.38 – 7.26 (m, 2H), 7.27 – 7.18 (m, 2H), 7.17 – 7.06 (m, 2H), 6.70 (m,
2H), 6.23 (t, 2H (minor)), 6.19 (t, 2H (major)), 4.1 (m, 1H (major)) , 4.05 (m, 1H (minor)), 3.72 (s, 1H (minor)), 3.54 (3H
(
major)), 2.88 (1H), 2.52 – 2.34 (2H), 2.30 – 1.98 (2H), 1.23 (3H (major)), 0.94 (3H (minor)). 13C{1H} NMR (101 MHz,
CDCl
3
) δ 175.0, 174.5, 141.02, 140.97, 128.5, 128.4, 126.1, 126.0, 119.5, 119.4, 108.3, 108.0, 61.5, 61.4, 51.9, 51.8,
+
46.7, 46.5, 35.9, 33.8, 32.2, 32.0, 14.6, 14.4. HRMS [EI]: m/z calculated for C17
H
21NO
2
[M] 271.1567, found 271.1568.
-1
IR (ATR): ν= 2951 (w), 1732 (s), 1265 (m), 1161 (m), 721 (vs), 698 (vs) cm .
methyl 3-cyclohexyl-2-methyl-3-(1H-pyrrol-1-yl)propanoate (9ta). Yield: colorless oil, 59 mg, 0.237 mmol. Mixture
1
of diastereomers. H NMR (400 MHz, CDCl
3
) δ 6.61 (m, 2H), 6.12 (m, 2H), 3.99 (dd, J = 8.6, 7.0 Hz, 1H (minor)), 3.89
(dd, J = 8.2, 6.6 Hz, 01H (major)), 3.71 (s, 3H (minor)), 3.57 (s, 3H (major)), 3.22 – 2.95 (m, 1H), 1.89 (dddd, J = 11.7,
8
2
6
.7, 6.5, 3.3 Hz, 1H), 1.82 – 1.44 (m, 6H), 1.22 (d, J = 7.0 Hz, 3H), 1.18 – 1.07 (m, 2H (major)), 1.01 (d, J = 7.0 Hz,
H(minor)), 0.96 – 0.77 (m, 1H). 13C{1H} NMR (101 MHz, CDCl
) δ 175.3, 174.7, 120.8, 120.6, 107.5, 107.1, 67.4,
3
6.8, 51.9, 51.7, 42.5, 42.0, 41.2, 39.4, 30.9, 30.6, 28.7, 28.0, 26.3, 26.24, 26.21, 26.17, 26.12, 15.0, 13.49.HRMS [EI]:
+
m/z calculated for C15
H
23NO
2
[M] 249.1729, found 249.1724. IR (ATR): ν= 2973 (m), 2855 (m), 1735 (s), 1261 (m),
-1
1165 (m), 721 (vs) cm .
methyl 3-(4-methoxyphenyl)-2-methyl-3-(1H-pyrrol-1-yl)propanoate (9fa). Yield: colorless oil, 20.2 mg,
1
0.074 mmol. Mixture of diastereomers. H NMR (400 MHz, CDCl
3
) δ 7.37 – 7.23 (m, 2H), 6.99 – 6.82 (m, 2H), 6.76 (m,
2H), 6.16 (m, 2H (minor)), 6.11 (m, 2H (major)), 5.16 (m, 1H), 3.80 (m, 3H), 3.60 (s, 3H (major)), 3.56 (s, 3H (minor)),
3
.43 (m, 1H), 1.14 (m, 3H). 13C{1H} NMR (101 MHz, CDCl
3
) δ 174.9, 174.5, 159.4, 159.2, 131.7, 130.8, 129.9, 128.6,
128.2, 119.5, 119.3, 114.2, 114.0, 113.8, 108.5, 108.2, 65.7, 65.1, 55.3, 55.2, 52.1, 51.9, 45.3, 45.1, 29.7, 16.0, 15.6.
+
HRMS [EI]: m/z calculated for C16H19NO
3
[M] 273.1359, found 273.1355. IR (ATR): ν= 2951 (w), 1735 (s), 1512 (s),
-1
1250 (m), 1165 (s), 723 (vs), 629 (s) cm .
methyl (syn)-2-methyl-3-(naphthalen-2-yl)-3-(1H-pyrrol-1-yl)propanoate (syn 9sa). Yield: colorless solid,
1
47.4 mg, 0.162 mmol, 41%. H NMR (400 MHz, CDCl
3
) δ 7.86 – 7.79 (m, 3H), 7.58 – 7.42 (m, 3H), 6.84 (t, J = 2.2 Hz,
13
2H), 6.20 (t, J = 2.1 Hz, 2H), 5.39 (d, J = 11.0 Hz, 1H), 3.67 – 3.59 (m, 1H), 3.55 (s, 3H), 1.23 (d, J = 6.9 Hz, 3H). C{1H}
NMR (101 MHz, CDCl
3
) δ 174.5, 136.8, 133.2, 133.0, 128.7, 128.2, 127.6, 126.3, 126.3, 125.6, 125.3, 119.8, 108.7,
+
65.6, 52.0, 44.9, 15.7. HRMS [EI]: m/z calculated for C19
H
19NO
2
[M] 293.1410, found 293.1414. IR (ATR): ν= 2935
w), 1720 (vs), 1357 (m), 1269 (m), 1177 (m), 725 (vs), 383 (vs) cm-1.
(
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methyl (anti)-2-methyl-3-(naphthalen-2-yl)-3-(1H-pyrrol-1-yl)propanoate (anti 9sa). Yield: colorless solid,
1
2
1
1
5.0 mg, 0.085 mmol, 21%. H NMR (400 MHz, CDCl
3
) δ 7.92 – 7.78 (m, 4H), 7.55 – 7.49 (m, 2H), 7.44 (dd, J = 8.5,
.8 Hz, 1H), 6.86 (t, J = 2.2 Hz, 2H), 6.14 (t, J = 2.2 Hz, 2H), 5.40 (d, J = 11.2 Hz, 1H), 3.65 (s, 3H), 3.62 – 3.54 (m,
13
H), 1.17 (d, J = 7.0 Hz, 3H). C{1H} NMR (101 MHz, 0CDCl
3
) δ 174.9, 136.0, 133.2, 133.1, 129.0, 128.03, 128.02,
[M]+
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
127.7, 126.8, 126.5, 126.4, 124.6, 119.5, 108.4, 66.4, 52.2, 44.8, 16.1. HRMS [EI]: m/z calculated for C19
H
19NO
2
-
1
2
93.1410, found 293.1413. IR (ATR): ν= 2936 (w), 1728 (s), 1258 (m), 1161 (m), 725 (vs), 687 (m) cm .
methyl 3-(4-fluorophenyl)-2-methyl-3-(1H-pyrrol-1-yl)propanoate (9na). Yield: colorless oil, 18.9 mg, 0.07 mmol.
1
Mixture of diastereomers. H NMR (400 MHz,CDCl
3
) δ 7.32 (m, 2H), 7.14 – 6.96 (m, 2H), 6.76 (m, 2H), 6.18 (m, 2H),
) δ
74.6, 174.3, 162.4 (d, J = 247.4 Hz), 134.6, 134.6, 129.0 (d, J = 8.3 Hz), 128,7 (d, J = 8.2 Hz), 119.5, 119.3, 115.8 (d,
J = 21.4 Hz), 115.6 (d, J = 21.6 Hz), 108.8, 108.5, 65.5, 65.0, 52.2, 52.0, 45.2, 45.0, 16.0. 19F NMR (377 MHz, CDCl
5.19 (m, 1H), 3.61 (s, 3H (major)), 3.56 (s, 3H (minor)), 3.42 (m, 1H), 1.13 (m, 3H). 13C{1H} NMR (101 MHz, CDCl
3
1
3
)
+
δ -113.74, -114.01. HRMS [EI]: m/z calculated for C15
H16NFO
2
[M] 261.1160, found 261.1162. IR (ATR): ν= 2951 (w),
-1
1753 (s), 1512 (s), 1265 (m), 1161 (s), 721 (vs), 623 (s) cm .
methyl 3-(4-trifluoromethyl)-2-methyl-3-(1H-pyrrol-1-yl)propanoate (9ka). Yield: colorless oil, 46.5 mg, 0.15 mmol.
1
Mixture of diastereomers. H NMR (250 MHz, CDCl
3
) δ 7.62 (m, 2H), 7.46 (m, 2H), 6.78 (m, 2H), 6.18 (m, 2H), 5.28 (m,
) δ
175.2, 175.0, 143.6, 131.4 (q, JC-F = 32.4 Hz) 128.6, 128.3, 126.8 (q, JC-F = 3.8 Hz), 120.5, 120.3, 110.0, 109.7, 66.6,
1
H), 3.64 (s, 3H (major)), 3.58 (s, 3H (minor)), 3.55 – 3.39 (m, 1H), 1.17 (m, 3H). 13C{1H} NMR (63 MHz, CDCl
3
3
66.0, 53.2, 53.0, 45.7, 45.5, 16.8, 16.4. 19F NMR (377 MHz, CDCl ) δ -62.72. HRMS [EI]: m/z calculated for
+
C
16
H
16NF
3
O
2
[M] 311.1128, found 311.1131. IR (ATR): ν= 2954 (w), 1736 (s), 1250 (m), 1323 (vs), 1165 (s), 1068 (vs)
-1
cm .
methyl
4-(3-methoxy-2-methyl-3-oxo-1-(1H-pyrrol-1-yl)propyl)benzoate
(9ia).
Yield:
colorless
solid,
1
4
5 mg, 0.15 mmol, >99%. Mixture of diastereomers. H NMR (400 MHz, CDCl
3
) δ 8.02 – 7.86 (m, 2H), 7.38 – 7.26 (m,
2
H), 6.66 (m, 2H), 6.07 (m, 2H (minor)), 6.02 (m, 2H (major)), 5.15 (m, 1H), 3.81 (m, 3H), 3.51 (s, 3H (major)), 3.44 (s,
) δ 174.4, 174.1, 166.5,
66.5, 144.3, 143.6, 130.2, 130.1, 130.0, 129.9, 127.4, 127.0, 119.6, 119.4, 108.9, 108.7, 65.8, 65.3, 52.2, 52.1, 52.0,
3H (minor)), 3.36 (m, 1H) 1.07 (2H (minor)), 1.02 (2H (major)). 13C{1H} NMR (101 MHz, CDCl
3
1
4
+
4.9, 44.6, 15.9, 15.5. HRMS [ESI]: m/z calculated for C17H19NO
4
[M] 301.1317 found 301.1314. IR (ATR): ν= 2951
w), 1720 (vs), 1435 (m), 1276 (vs), 1168 (m), 725 (m) cm-1.
(
methyl 3-(4-cyanophenyl)-2-methyl-3-(1H-pyrrol-1-yl)propanoate (9ja). Yield: colorless oil, 41.2 mg, 0.153 mmol.
1
Mixture of diastereomers. H NMR (250 MHz, CDCl
3
) δ 7.65 (m, 2H), 7.44 (m, 2H), 6.75 (m, 2H), 6.27 – 6.08 (m, 2H),
5
.39 – 5.18 (m, 1H), 3.63 (s, 3H (major)), 3.58 (s, 3H (minor)), 3.44 (m, 1H), 1.17 (3H). 13C{1H} NMR (63 MHz, CDCl
)
3
δ 175.0, 174.9, 145.5, 144.7, 133.7, 133.5, 128.9, 128.6, 120.5, 120.3, 119.2, 113.2, 113.0, 110.2, 110.0, 66.5, 66.0,
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16 2 2
3.2, 53.1, 45.6, 45.3, 30.6, 16.8, 16.4. HRMS [EI]: m/z calculated for C16H N O [M] 268.1206, found 268.1208. IR
-1
(ATR): ν= 2955 (w), 2230 (w), 1732 (s), 1269 (m), 1168 (m), 721 (vs) cm .
General procedure for intramolecular Friedel craft acylation. Under nitrogen, the substrate (1.equiv.) was dissolved
in CH Cl (0.1M) and BBr (1.05 eq.) was added slowly. The reaction was monitored by TLC and when judged
completed, poured onto sat. NaHCO solution. The organic phase was separated, and the aqueous phase was
extracted twice with CH Cl . The combined organic phases were dried over Na SO and after evaporation subjected
to column chromatography to yield the desired compound.
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(
2S,3R)-2-methyl-3-phenyl-2,3-dihydro-1H-pyrrolizin-1-one (trans-7ba). Yield: colorless oil, 74.9 mg, 0.35 mmol,
1
53%. Chromatography: ethyl acetate: petroleum ether 15:85 H NMR (250 MHz, CDCl
3
) δ 7.46 – 7.37 (m, 3H), 7.26 –
7
1
1
.17 (m, 2H), 6.82 (d, J = 2.1 Hz, 2H), 6.56 (dd, J = 3.8, 2.5 Hz, 1H), 5.02 (d, J = 4.8 Hz, 1H), 2.98 (qd, J = 7.4, 4.8 Hz,
H), 1.44 (d, J = 7.4 Hz, 3H). 13C{1H} NMR (63 MHz, CDCl
) δ 192.0, 140.3, 133.7, 130.2, 129.6, 127.3, 123.2, 118.1,
3
+
08.9, 67.5, 57.1, 15.1. HRMS [ESI]: m/z calculated for C14H
13NNaO [M+Na] 234.0894, found 234.0896. IR (ATR): ν=
-1
2966 (w), 1693 (vs), 1523 (m), 1454 (m), 1307 (s), 736 (vs), 798 (vs) cm .
(
2S,3S)-2-methyl-3-phenyl-2,3-dihydro-1H-pyrrolizin-1-one (cis-7ba). Yield: colorless solid, 13.0 mg, 0.06 mmol,
1
1
0%. Chromatography: ethyl acetate: petroleum ether 15:85 H NMR (400 MHz, CDCl
3
) δ 7.34 (dd, J = 5.8, 1.6 Hz,
3
H), 6.92 (dd, J = 2.3, 1.1 Hz, 1H), 6.85 (dd, J = 3.8, 1.2 Hz, 3H), 6.61 (dd, J = 4.0, 2.3 Hz, 1H), 5.72 (d, J = 8.0 Hz,
1H), 3.50 (p, J = 7.7 Hz, 1H), 0.86 (d, J = 7.6 Hz, 3H). 13C{1H} NMR (63 MHz, CDCl3) δ 191.6, 138.3, 132.7, 128.8,
1
28.4, 126.9, 122.8, 117.2, 107.5, 62.6, 50.5, 12.1. IR (ATR): ν= 2970 (w), 2018 (w), 1693 (vs), 1524 (m), 1369 (m),
-1
1307 (m), 741 (s), 698 (s) in cm .
(
2S,3R)-3-(3,5-dimethylphenyl)-2-methyl-2,3-dihydro-1H-pyrrolizin-1-one (trans-7ea). Yield: colorless oil,
1
11.3 mg, 0.047 mmol, 53%. Chromatography: ethyl acetate: petroleum ether 15:85 H NMR (250 MHz, CDCl
3
) δ 7.03
(
s, 1H), 6.91 – 6.77 (m, 4H), 6.58 (dd, J = 3.7, 2.6 Hz, 1H), 4.94 (d, J = 4.8 Hz, 1H), 2.99 (qd, J = 7.4, 4.8 Hz, 1H), 2.34
(
s, 6H), 1.44 (d, J = 7.4 Hz, 3H). 13C{1H} NMR (63 MHz, CDCl
3
) δ 186.9, 134.9, 134.5, 128.3, 125.9, 119.8, 117.9,
+
112.6, 103.5, 62.2, 51.7, 16.9, 9.8. HRMS [ESI]: m/z calculated for C16
H
18NO [M+H] 240.1383, found 240.1338. IR
-1
(ATR): ν= 2924 (w), 1697 (vs), 1527 (m), 1369 (m), 1307 (m), 848 (m), 741 (vs) cm . This compound was subjected to
the conventional self-disproportionation of enantiomers (SDE) test described in the literature.20 We did not observe
significant SDE for this compound and there were no indications of significant SDE with other pyrrolizin-1-one and N-
allyl pyrroles reported here.
trans-2-methyl-3-phenethyl-2,3-dihydro-1H-pyrrolizin-1-one
(trans-7ua).
Yield:
colorless
solid,
1
7
.5 mg, 0.040 mmol, 55% (brsm). Chromatography: ethyl acetate: petroleum ether 10:90 H NMR (400 MHz, CDCl
3
)
δ 7.34 (dd, J = 8.0, 6.6 Hz, 2H), 7.30 – 7.20 (m, 3H), 7.05 (dd, J = 2.3, 1.0 Hz, 1H), 6.76 (dd, J = 4.0, 1.0 Hz, 1H), 6.56
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(
dd, J = 4.0, 2.3 Hz, 1H), 4.15 (dt, J = 8.1, 4.2 Hz, 1H), 2.87 (qd, J = 7.4, 3.9 Hz, 1H), 2.82 – 2.66 (m, 2H), 2.46 – 2.30
13
(m, 1H), 2.24 – 2.05 (m, 1H), 1.42 (d, J = 7.4 Hz, 3H). C{1H} NMR (101 MHz, CDCl
3
) δ 191.9, 140.4, 132.2, 128.7,
+
1
28.2, 126.4, 121.5, 116.9, 107.8, 62.1, 51.7, 37.2, 31.4, 15.9. HRMS [EI]: m/z calculated for C16
H
17NO [M] 239.1305,
-1
found 239.1303. IR (ATR): ν= 2928(w), 1693 (vs), 1523 (vs), 1307 (s), 736 (vs) cm .
1
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trans-3-cyclohexyl-2-methyl-2,3-dihydro-1H-pyrrolizin-1-one
(trans-7ta).
Yield:
colorless
oil,
2
4.6 mg, 0.113 mmol, 62%. Chromatography: ethyl acetate: petroleum ether 10:90 1H NMR (300 MHz, CDCl
3
) δ 7.01
(s, 1H), 6.70 (d, J = 4.0 Hz, 1H), 6.52 (dd, J = 4.0, 2.3 Hz, 1H), 4.00 (t, J = 3.8 Hz, 2H), 2.85 (qd, J = 7.5, 3.3 Hz, 2H),
.99 – 1.63 (m, 4H), 1.35 (d, J = 7.5 Hz, 3H), 1.31 – 1.14 (3H) 1.12 - 0.97 (m, 3H), 0.87 (m, 2H). 13C{1H} NMR (75
1
MHz, CDCl
3
) δ 192.6, 132.4, 122.0, 116.61, 107.3, 67.4, 48.1, 42.4, 29.7, 28.9, 26.8, 26.3, 26.1, 25.9, 17.0. HRMS [EI]:
+
m/z calculated for C14
H
19NO [M] 217.1467, found 217.1463. IR (ATR): ν= 2824 (m), 2855 (m), 1693 (vs), 1527 (m),
-1
1
369 (m), 1307 (m), 733 (vs) cm .
trans-3-(4-methoxyphenyl)-2-methyl-2,3-dihydro-1H-pyrrolizin-1-one
(trans-7fa).
Yield:
colorless
oil,
1
5.0 mg, 0.023 mmol, 32%. Chromatography: ethyl acetate: petroleum ether 30:70 H NMR (600 MHz, CDCl
3
) δ 7.05
(d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.73 (dd, J = 3.9, 1.1 Hz, 1H), 6.71 (dd, J = 2.4, 1.0 Hz, 1H), 6.46 (dd, J =
13
3
.9, 2.3 Hz, 1H), 4.87 (d, J = 5.0 Hz, 1H), 3.75 (s, 3H), 2.88 (qd, J = 7.4, 5.0 Hz, 1H), 1.33 (d, J = 7.4 Hz, 3H). C{1H}
NMR (151 MHz, CDCl
[EI]: m/z calculated for C15
vs), 1030 (m), 736 (s), 613 (m) cm .
trans-2-methyl-3-(naphthalen-2-yl)-2,3-dihydro-1H-pyrrolizin-1-one
.8 mg, 0.018 mmol, 24% (brsm). Chromatography: ethyl acetate: petroleum ether 15:85 H NMR (400 MHz, CDCl
3
) δ 191.3, 159.9, 132.7, 131.2, 127.8, 122.1, 117.1, 114.6, 107.9, 66.2, 56.2, 55.4, 14.0.. HRMS
+
H
15NO
2
[M] 241.1097, found 241.1095. IR (ATR): ν= 2931 (w), 1693 (vs), 1512 (vs), 1249
-1
(
(trans-7sa).
Yield:
colorless
solid,
) δ
1
4
3
7.95 – 7.84 (m, 3H), 7.75 (d, J = 1.7 Hz, 1H), 7.63 – 7.50 (m, 2H), 7.22 (dd, J = 8.5, 1.9 Hz, 1H), 6.89 (dd, J = 3.9, 1.1
Hz, 1H), 6.84 (dd, J = 2.3, 1.1 Hz, 1H), 6.60 (dd, J = 4.0, 2.3 Hz, 1H), 5.19 (d, J = 4.9 Hz, 1H), 3.10 (qd, J = 7.4, 4.9
13
Hz, 1H), 1.49 (d, J = 7.4 Hz, 3H). C{1H} NMR (101 MHz, CDCl
3
) δ 191.1, 136.5, 133.3, 133.2, 129.6, 127.9, 127.9,
15NO [M]+
126.8, 126.8, 126.1, 123.4, 122.3, 117.3, 108.1, 66.9, 56.0, 14.2. HRMS [EI]: m/z calculated for C18
H
-1
261.1148, found 261.1152. IR (ATR): ν= 2928 (w), 1693 (m), 1527 (m), 1572 (m), 1366 (m), 1308 (s), 736 (vs) cm .
trans-3-(4-fluorophenyl)-2-methyl-2,3-dihydro-1H-pyrrolizin-1-one
(trans-7na).
Yield:
colorless
solid,
1
9
.4 mg, 0.041 mmol, 53%. Chromatography: ethyl acetate: petroleum ether 20:80 H NMR (400 MHz, CDCl
3
) δ 7.19
(m 2H), 7.11 (m2H), 6.84 (dd, J = 4.0, 1.1 Hz, 1H), 6.82 – 6.79 (m, 1H), 6.58 (dd, J = 4.0, 2.3 Hz, 1H), 5.01 (d, J = 4.8
Hz, 1H), 2.95 (qd, J = 7.4, 4.9 Hz, 1H), 1.44 (d, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl
3
) δ 190.8, 162.8 (d, JC-F
=
247.9 Hz), 135.2 (d, JC-F = 3.1 Hz), 132.7, 128.2 (d, JC-F = 8.4 Hz), 122.1, 117.3, 116.3 (d, JC-F = 21.7 Hz), 108.1,
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+
6
6.0, 56.2, 14.2. HRMS [EI]: m/z calculated for C14H
12NFO [M] 229.0897, found 229.0899. IR (ATR): ν= 2931 (w),
-1
1705 (s), 1512 (m), 1288 (m), 1010 (m), 829 (vs), 775 (s) cm .
cis-3-(4-fluorophenyl)-2-methyl-2,3-dihydro-1H-pyrrolizin-1-one
(cis-7na).
Yield:
colorless
solid,
1
1
2
0
.2 mg, 0.005 mmol, 7%. Chromatography: ethyl acetate: petroleum ether 20:80 H NMR (300 MHz, CDCl
3
) δ 7.03 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
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2
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6
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H), 6.90 (m, 1H), 6.89 – 6.77 (m, 2H), 6.60 (dd, J = 4.0, 2.3 Hz, 1H), 5.71 (d, J = 8.0 Hz, 1H), 3.48 (p, J = 7.7 Hz, 1H),
.85 (d, J = 7.6 Hz, 3H). 19F NMR (377 MHz, CDCl
) δ -113.37. HRMS [EI]: m/z calculated for C14
H
12NFO [M] 229.0897,
+
3
found 229.0900.
trans-3-(4-trifluormethylphenyl)-2-methyl-2,3-dihydro-1H-pyrrolizin-1-one (trans-7ka). Yield: colorless solid,
1
12.2 mg, 0.044 mmol, 30%. Chromatography: ethyl acetate: petroleum ether 15:85 H NMR (250 MHz, CDCl
3
) δ 7.70
(
d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.89 – 6.86 (m, 1H), 6.83 (dd, J = 2.4, 1.0 Hz, 1H), 6.61 (dd, J = 3.9, 2.4
13
Hz, 1H), 5.11 (d, J = 4.8 Hz, 1H), 2.97 (qd, J = 7.4, 4.8 Hz, 1H), 1.48 (d, J = 7.4 Hz, 3H).). C{1H} NMR (63 MHz,
CDCl3) δ 191.2, 144.4, 133.7, 132.0 (q, JC-F=32.5 Hz), 127.6, 127.2 (q, JC-F = 3.76Hz), 124.7 (q, JC-F = 272 Hz), 118.5,
109.3, 67.0, 57.1, 15.2. 19F NMR (377 MHz, CDCl
found 279.0862. IR (ATR): ν= 2970 (w), 1697 (m), 1528 (vs), 1312 (vs), 1065 (vs), 1018 (m), 734 (m) cm .
trans-3-(4-cyanophenyl)-2-methyl-2,3-dihydro-1H-pyrrolizin-1-one (trans-7ia). Yield: colorless
.2 mg, 0.030 mmol, 22% (brsm). Chromatography: ethyl acetate: petroleum ether 20:80 H NMR (400 MHz, CDCl
δ 7.72 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.86 (dd, J = 4.0, 1.1 Hz, 1H), 6.82 (dd, J = 2.4, 1.0 Hz, 1H), 6.61
) δ -62.72. HRMS [EI]: m/z calculated for C15
H
12NF
O [M] 279.0866,
+
3
3
-1
solid,
1
7
3
)
(
dd, J = 4.0, 2.4 Hz, 1H), 5.10 (d, J = 4.7 Hz, 1H), 2.92 (qd, J = 7.4, 4.7 Hz, 1H), 1.47 (d, J = 7.4 Hz, 3H). 13C{1H} NMR
101 MHz, CDCl ) δ 189.9, 144.8, 133.2, 132.7, 127.0, 122.1, 118.1, 117.9, 112.8, 108.5, 66.0, 56.1, 14.5. HRMS [EI]:
(
3
+
12 2
m/z calculated for C15H N
O [M] 236.0944, found 236.0945. IR (ATR): ν= 2927 (w), 1701 (vs), 1458 (m), 1369 (m),
-1
1281 (vs), 744 (m) cm .
trans-methyl 4-(trans)-2-methyl-1-oxo-2,3-dihydro-1H-pyrrolizin-3-yl)benzoate (trans-7ja). Yield: colorless solid,
1
1
6.9 mg, 0.063 mmol, 46% (brsm). Chromatography: ethyl acetate: petroleum ether 20:80 H NMR (600 MHz, CDCl
3
)
δ 8.07 – 7.96 (m, 2H), 7.17 (d, J = 8.3 Hz, 2H), 6.76 (d, J = 4.0 Hz, 1H), 6.73 (d, J = 1.3 Hz, 1H), 6.50 (dd, J = 4.0, 2.3
Hz, 1H), 5.00 (d, J = 4.8 Hz, 1H), 3.86 (s, 3H), 2.87 (qd, J = 7.4, 4.8 Hz, 1H), 1.37 (d, J = 7.4 Hz, 3H). 13C{1H} NMR
(151 MHz, CDCl
3
) δ 190.5, 166.4, 144.4, 132.7, 130.6, 130.6, 126.3, 122.2, 117.5, 108.3, 66.2, 56.1, 52.3, 14.4. HRMS
+
[
EI]: m/z calculated for C16
H
15NO
3
[M] 269.1052, found 269.1053.
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The Supporting Information is available free of charge on the ACS Publications website at DOI:
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0.1021/acs.joc.XXXXXXX. 1H, 13C, and 19F NMR of new compounds, 1H NMR spectra of known
compounds and HPLC chromatograms for compounds prepared in enantioenriched form.
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Acknowledgment
Financial support from the Carl-Zeiss Foundation (endowed professorship to I.V.), Friedrich Schiller
University Jena and the State of Thuringia (graduate fellowship to M.L.) is gratefully acknowledged. We
thank Philipp Schüler, Dr. Peter Bellstedt, and Dr. Nico Ueberschaar for their support with HPLC, NMR,
and MS analysis, respectively. The help of Constanze Schultz, Lea Klepsch and Hannah Zeihe in the
synthesis of starting materials is greatly appreciated.
References and Notes
(1)
a) Liddell, J. R. Pyrrolizidine alkaloids Nat. Prod. Rep. 2002, 19, 773; b) Robertson, J.; Stevens, K.
Pyrrolizidine alkaloids Nat. Prod. Rep. 2014, 31, 1721; c) Gouda, A. M.; Abdelazeem, A. H. An integrated overview on
pyrrolizines as potential anti-inflammatory, analgesic and antipyretic agents Eur. J. Med. Chem. 2016, 114, 257;
d) Robertson, J.; Stevens, K. Pyrrolizidine alkaloids: occurrence, biology, and chemical synthesis Nat. Prod.
Rep. 2017, 34, 62.
(
2)
a) Usuki, H.; Toyo-oka, M.; Kanzaki, H.; Okuda, T.; Nitoda, T. Pochonicine, a polyhydroxylated
potent β-N-
pyrrolizidine alkaloid from fungus Pochonia suchlasporia var. suchlasporia TAMA 87 as
a
acetylglucosaminidase inhibitor Biorg. Med. Chem. 2009, 17, 7248; b) Kitamura, Y.; Koshino, H.; Nakamura, T.;
Tsuchida, A.; Nitoda, T.; Kanzaki, H.; Matsuoka, K.; Takahashi, S. Total synthesis of the proposed structure for
pochonicine and determination of its absolute configuration Tetrahedron Lett. 2013, 54, 1456; c) Zhu, J.-S.; Nakagawa,
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