A palladium iodide-catalyzed carbonylative approach to functionalized pyrrole derivatives

Article abstract of DOI:10.1021/jo300365n

A novel and convenient approach to functionalized pyrroles is presented, based on Pd-catalyzed oxidative heterocyclization-alkoxycarbonylation of readily available N-Boc-1-amino-3-yn-2-ols. Reactions were carried out in alcoholic solvents at 80-100 °C and under 20 atm (at 25 °C) of a 4:1 mixture of CO-air, in the presence of the PdI₂-KI catalytic system (2-5 mol % of PdI₂, KI/PdI₂ molar ratio = 10). In the case of N-Boc-1-amino-3-yn-2-ols 3, bearing alkyl or aryl substituents, the carbonylation reaction led to a mixture of Boc-protected and N-unsubstituted pyrrole-3-carboxylic esters 4 and 5, respectively. This mixture could be conveniently and quantitatively converted into deprotected pyrrole-3-carboxylic esters 5 by a simple basic treatment. In the case of diastereomeric (3RS,4RS)- and (3RS,4SR)-N-Boc-3-amino-2-methyldec-5-yn-4-ol (syn-3f and anti-3f, respectively, whose relative configuration was determined by X-ray crystallographic analysis), no particular difference was observed in the reactivity of the two diastereomers between them and with respect to the diastereomeric mixture (3S,4S) + (3S,4R). Interestingly, N-Boc-2-alkynyl-1- amino-3-yn-2-ols 6, bearing an additional alkynyl substituent α to the hydroxyl group, spontaneously underwent N-deprotection under the reaction conditions and regioselective water addition to the alkynyl group at C-3 of the corresponding pyrrole-3-carboxylic ester derivative, thus directly affording highly functionalized pyrrole derivatives 7 in one step. In a similar manner, a novel functionalized dihydropyrrolizine derivative 9 was directly synthesized starting from (S)-7-(pyrrolidin-2-yl)trideca-5,8-diyn-7-ol 8.

Full text of DOI:10.1021/jo300365n

Article
pubs.acs.org/joc
A Palladium Iodide-Catalyzed Carbonylative Approach to
Functionalized Pyrrole Derivatives
Bartolo Gabriele,*,† Lucia Veltri,‡ Raffaella Mancuso,‡ Giuseppe Salerno,‡ Sabino Maggi,§
and Brunella Maria Aresta§
†Dipartimento di Scienze Farmaceutiche, Universita
̀
della Calabria, 87036 Arcavacata di Rende (CS), Italy
‡Dipartimento di Chimica, Universita
̀
della Calabria, 87036 Arcavacata di Rende (CS), Italy
§Istituto di Cristallografia, CNR, 70124 Via Amendola, 122/O, Bari, Italy
S
* Supporting Information
ABSTRACT: A novel and convenient approach to function-
alized pyrroles is presented, based on Pd-catalyzed oxidative
heterocyclization−alkoxycarbonylation of readily available
N-Boc-1-amino-3-yn-2-ols. Reactions were carried out in
alcoholic solvents at 80−100 °C and under 20 atm (at 25 °C)
of a 4:1 mixture of CO−air, in the presence of the PdI2−KI
catalytic system (2−5 mol % of PdI2, KI/PdI2 molar ratio = 10).
In the case of N-Boc-1-amino-3-yn-2-ols 3, bearing alkyl or
aryl substituents, the carbonylation reaction led to a mixture of
Boc-protected and N-unsubstituted pyrrole-3-carboxylic esters
4 and 5, respectively. This mixture could be conveniently and quantitatively converted into deprotected pyrrole-3-carboxylic
esters 5 by a simple basic treatment. In the case of diastereomeric (3RS,4RS)- and (3RS,4SR)-N-Boc-3-amino-2-methyldec-5-yn-
4-ol (syn-3f and anti-3f, respectively, whose relative configuration was determined by X-ray crystallographic analysis), no
particular difference was observed in the reactivity of the two diastereomers between them and with respect to the diastereomeric
mixture (3S,4S) + (3S,4R). Interestingly, N-Boc-2-alkynyl-1-amino-3-yn-2-ols 6, bearing an additional alkynyl substituent α to
the hydroxyl group, spontaneously underwent N-deprotection under the reaction conditions and regioselective water addition to
the alkynyl group at C-3 of the corresponding pyrrole-3-carboxylic ester derivative, thus directly affording highly functionalized
pyrrole derivatives 7 in one step. In a similar manner, a novel functionalized dihydropyrrolizine derivative 9 was directly
synthesized starting from (S)-7-(pyrrolidin-2-yl)trideca-5,8-diyn-7-ol 8.
In particular, the PdI2/KI catalytic system has proved valuable for
the direct synthesis of a variety of carbonylated heterocyclic
derivatives starting from suitably functionalized alkynes, by either a
cyclocarbonylation or a cyclization−carbonylation pathway.2−6 Very
recently, we have reported that furan-3-carboxylic esters 2 can be
obtained in good yields (56−72%) by PdI2/KI-catalyzed 5-endo-dig
heterocyclodehydration-alkoxycarbonylation of 3-yne-1,2-diols 1
(Scheme 2, Y = O).2c Reactions were carried out in alcoholic
solvents at 100 °C and under 40 atm of a 4:1 mixture of CO−air.
In this study, we have investigated the reactivity of N-Boc-1-
amino-3-yn-2-ols 3 under similar conditions, to verify if the
methodology could be also applied to the synthesis of N-Boc-
pyrrole-3-carboxylic esters 4 and, after deprotection, of N-un-
substituted pyrrole-3-carboxylic esters 5. Pyrrole-3-carboxylic ester
derivatives represent, in fact, a particularly important subclass of
pyrrole derivatives,7 which have been so far obtained by synthetic
methods not involving a direct carbonylation approach.8
INTRODUCTION
■
The PdI2−KI catalytic system, introduced by our research group
about 20 years ago,1 is now established as one of the most efficient
and versatile catalysts for the oxidative carbonylation of simple and
functionalized alkynes1−3 as well as of amines,4 amino alcohols,5
and diols,6 with only oxygen as oxidizing agent. The main success
of this system is due to the very efficient mechanism for the
reoxidation of the Pd(0) species ensuing from the oxidative
carbonylation process, which occurs through oxidative addition of
I2, formed in its turn by oxidation of the HI also ensuing from the
process (Scheme 1; anionic iodide ligands are omitted for clarity;
SH2 = substrate).1−3
Scheme 1. Mechanism of Pd(0) Reoxidation in PdI2-
Catalyzed Oxidative Carbonylation Reactions
a
Received: February 22, 2012
Published: March 22, 2012
a
SH2 = organic substrate(s).
© 2012 American Chemical Society
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Scheme 2. PdI2/KI-Catalyzed Formation of Furan-3-carboxylic Esters 2 and Pyrrole-3-carboxylic Esters 4 and 5 by Oxidative
Carbonylation of 3-Yne-1,2-diols 1 or N-Boc-1-amino-3-yn-2-ols 3, Respectively
Table 1. PdI2/KI-Catalyzed Oxidative Carbonylation Reactions of N-Boc-2-amino-1-phenylnon-4-yn-3-ol 3a Under Different
a
Conditions
b
c
c
entry
KI:PdI2 molar ratio
T (°C)
substrate concentration
time (h)
yield of 4a (%)
yield of 5a (%)
total yield (%)
70
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
50
5
80
80
0.20
0.20
0.20
0.20
0.05
0.50
0.20
0.20
0.20
0.20
3
2
3
3
3
3
3
3
3
3
4
4
66
47
14
38
57
49
42
55
47
60
d
51
100
60
18
32
d
38
80
57
54
57
65
65
80
5
15
10
18
80
80
2
80
e
f
10
10
80
60
a
Substrate 3a was directly used as a (2S,3S) and (2S,3R) mixture of diastereoisomers (see the Experimental Section for details). Unless otherwise noted, all
reactions were carried out in MeOH in the presence of 2 mol % of PdI2 under 20 atm (at 25 °C) of a 4:1 mixture CO−air. Unless otherwise noted,
b
c
substrate conversion was quantitative. mmol of starting 3a per mL of MeOH. Isolated yield based on starting 3a. The formation of unidentified
heavy products (chromatographically immobile materials) accounted for the difference between the substrate conversion and the product yield.
d
e
f
Substrate conversion was 70%. The reaction was carried out under 40 atm of a 4:1 mixture (at 25 °C) of CO−air. Substrate conversion was 79%.
With reference to the total yield of the carbonylated products
(4a + 5a), this initial result did not improve by changing the
reaction parameters, such as the reaction time (Table 1, entry 2),
temperature (Table 1, entries 3 and 4), substrate concentra-
tion (Table 1, entries 5 and 6), KI:PdI2 molar ratio (Table 1,
entries 7−9), and total pressure (Table 1, entry 10), even
though the reaction allowed the predominant formation of
product 5a under some conditions (Table 1, entries 4, 5, and 10).
In any case, a total conversion of 4a into 5a, with selective
formation of unprotected pyrrole-3-carboxylic ester 5a, could
be achieved by treating the crude reaction mixture with
NaOMe at 60 °C for 8 h.10 In this way, a 68% isolated yield of
5a was achieved by carrying out the carbonylation reaction
under the conditions reported in entry 1 (Table 1) followed by
basic treatment (Table 2, entry 1).
Having established a simple and efficient two-step protocol
for the synthesis of N-unprotected pyrrole-3-carboxylic ester 5a
starting from N-Boc-2-amino-1-phenylnon-4-yn-3-ol 3a, we
next assessed the generality of the process by applying this
procedure to other N-Boc-1-amino-3-yn-2-ols, variously sub-
stituted with different alkyl or aryl groups. The results obtained,
shown in Table 2, demonstrate that the process is quite general,
with the corresponding pyrrole-3-carboxylic esters being
consistently obtained in satisfactory yields (61−89%). In
some cases, better results were observed by carrying out the
RESULTS AND DISCUSSION
■
PdI2/KI-Catalyzed Oxidative Carbonylation of N-Boc-
1-amino-3-yn-2-ols Bearing Alkyl or Aryl Substituents
(3a−g). The reactivity of N-Boc-2-amino-1-phenylnon-4-yn-3-
ol 3a, easily obtained from Boc-protected L-phenylalaninal by
alkynylation with 1-hexynylmagnesium bromide (see the Exper-
imental Section for details), was investigated first. This substrate,
directly employed as a mixture of diastereoisomers (2S,3S) and
(2S,3R), was initially let to react at 80 °C in MeOH (substrate
concentration = 0.2 mmol per mL of MeOH) under 20 atm of a
4:1 mixture CO−air,9 in the presence of PdI2 (2 mol %) and KI
(KI/PdI2 molar ratio = 10). After 3 h, analysis of the reaction
mixture revealed a total substrate conversion and the formation
of two products, which were separated and identified as methyl
N-Boc-5-benzyl-2-butylpyrrole-3-carboxylate 4a (4% yield) and
methyl 5-benzyl-2-butyl-1H-pyrrole-3-carboxylate 5a (66% yield)
(Table 1, entry 1), thus confirming the validity of our initial work
hypothesis. In fact, formation of 4a can be rationalized by 5-endo-dig
intramolecular nucleophilic attack by nitrogen to the triple
bond coordinated to the metal center, followed by dehydration,
carbon monoxide insertion, and nucleophilic displacement by
MeOH (Scheme 2, Y = NBoc, R = Me), while N-unsubstitued
pyrrole 5a is clearly formed by deprotection of the nitrogen of
4a under the reaction conditions.
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Table 2. Synthesis of N-Unsubstituted Pyrrole-3-carboxylic Esters 5 by PdI2/KI-Catalyzed Oxidative Carbonylation of N-Boc-1-
ab
,
amino-3-yn-2-ols 3 Followed by Basic Treatment
c
c
d
entry
3
R1
R2
R3
R
PdI2 (mol %)
T (°C)
t (h)
yield of 4 (%)
yield of 5 (%)
overall yield of 5 (%)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
Bn
H
Me
H
H
H
H
H
H
H
H
Bu
Bu
Bu
Bu
Ph
Bu
Bu
Bu
Bu
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
2
2
5
2
2
2
5
5
5
2
80
80
3
3
3
2
2
2
2
2
2
2
4
71
44
54
47
15
31
31
29
53
66
20
18
16
34
44
49
50
53
12
68
89
Bn
e
H
80
61
e
Me
Me
i-Pr
i-Pr
i-Pr
i-Pr
Bn
100
100
100
100
100
100
100
70
e
80
f
58
f
3f
79
g
f
8
syn-3f
anti-3f
3g
80
h
f
9
81
i
10
65
a
All carbonylation reactions were carried out in ROH (0.20 mmol of starting 3 per mL of solvent) with a KI:PdI2 molar ratio = 10. With the
exception of entries 3, 8, and 9, all the starting 3 employed were (SS) + (SR) diastereomeric mixtures (see the Experimental Section for details).
b
Conversion of 3 was quantitative in all cases. Unless otherwise noted, the basic treatment was carried out on the carbonylation reaction crude by
adding to the mixture 4 equiv of NaOMe (with respect to starting 3) and allowing the resulting mixture to react at 60 °C for 8 h (see the
c
d
Experimental Section for details). Isolated yield based on starting 3, referred to the oxidative carbonylation step. Overall isolated yield based on
e
starting 3, referred to the oxidative carbonylation step followed by the one-pot basic treatment. The basic treatment was carried out by adding, to
the carbonylation crude, 4 equiv of NaOMe (with respect to starting 3) and allowing the resulting mixture to react at 25 °C for 15 h. The basic
treatment was carried out by adding, to the carbonylation crude, 16 equiv of NaOMe (with respect to starting 3f) and allowing the resulting mixture
to react at 25 °C for 72 h. The substrate employed was a racemic mixture of the syn-diastereomer, or (3RS,4RS)-diastereomer. The substrate
employed was a racemic mixture of the anti-diastereomer, or (3RS,4SR)-diastereomer. The basic treatment was carried out on the carbonylation
f
g
h
i
reaction crude by adding to the mixture 4 equiv of NaOEt (with respect to starting 3g) and allowing the resulting mixture to react at 60 °C for 8 h.
carbonylation step at 100 °C (Table 2, entries 4−10) or with a
higher catalyst loading (Table 2, entries 3, 7−9) and the
deprotection step at 25 °C rather than 60 °C (Table 2, entries
3−9). The process could also be carried out successfully in
EtOH rather than MeOH as reactant and solvent, as shown by
entry 10 (Table 2).
Scheme 3. PdI2/KI-Catalyzed Formation of 4-Acylpyrrole-3-
carboxylic Esters 7 by Oxidative Carbonylation of N-Boc-2-
alkynyl-1-amino-3-yn-2-ols 6
The influence of the substrate stereochemistry on the reaction
outcome was also investigated by reacting separately the two
racemic syn and anti diastereomers (3RS,4RS) and (3RS,4SR) of
N-Boc-3-amino-2-methyldec-5-yn-4-ol 3f (whose relative config-
uration was established by X-ray diffraction analysis; see the
Supporting Information for details), obtained from racemic valinal.
As shown in Table 2, entries 8 and 9, the two diastereomers gave
practically the same results, which were also comparable with that
obtained starting directly from the diastereomeric mixture (3S,4S) +
(3S,4R) (Table 2, entry 7), so it can be concluded that the
stereochemistry of the substrate does not significantly affect the
reaction outcome.
PdI2/KI-Catalyzed Oxidative Carbonylation of N-Boc-
2-alkynyl-1-amino-3-yn-2-ols (6a−g) and (S)-7-(Pyrroli-
din-2-yl)trideca-5,8-diyn-7-ol (8). Very interestingly, when
the oxidative carbonylation reaction was carried out on N-Boc-2-
alkynyl-1-amino-3-yn-2-ols 6, bearing an additional alkynyl
substituent α to the hydroxyl group, N-deprotection occurred
spontaneously under the reaction conditions, together with regio-
selective water addition to the triple bond of the alkynyl
substituent, with direct formation of polysubstituted and multi-
functionalized pyrrole derivatives 7 in one step (Scheme 3). The
regioselectivity of the water addition to the triple bond may be due
to the higher stability of the products obtained, in which the
carbonyl group is conjugated with the aromatic pyrrole ring.
Regarding the spontaneous N-deprotection, we refrain to suggest
a possible explanation, which would require additional inves-
tigation.
Thus, when (S)-N-Boc-7-(1-aminoethyl)-trideca-5,8-diyn-
7-ol 6a was allowed to react under conditions similar to
those previously employed for 3a (see Table 2, entry 1) (2
mol % of PdI2 in conjunction with 10 equiv of KI, at 100 °C
and in MeOH with a substrate concentration of 0.2 mmol of
6a per mL of MeOH, under a 4:1 mixture of CO−air), after
15 h the substrate conversion was complete, with selective
formation of 2-butyl-4-hexanoyl-5-methyl-1H-pyrrole-3-
carboxylate 7a in 70% isolated yield (Table 3, entry 1).
Under the same conditions, other differently substituted
N-Boc-2-alkynyl-1-amino-3-yn-2-ols, including highly hindered
substrates such as 6g and 6h, behaved similarly (Table 3,
entries 2−7), thus confirming the general applicability of the
process. The reaction could also be carried out in EtOH rather
than MeOH as the solvent, even though a higher catalyst
loading was required to achieve satisfactory results (Table 3,
entry 8).
Our methodology could also be successfully applied to un-
protected (S)-7-(pyrrolidin-2-yl)trideca-5,8-diyn-7-ol 8, deriv-
ing from L-proline methyl ester, which, under the same
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Table 3. Synthesis of 4-Acylpyrrole-3-carboxylic Esters 7 by PdI2/KI-Catalyzed Oxidative Carbonylation of 2-Alkynyl-1-amino-
a
3-yn-2-ols 6
a
Unless otherwise noted, all reactions were carried out in ROH (0.20 mmol of starting 6 per mL of solvent) in the presence of 2 mol % of PdI2 and
b
c
with a KI:PdI2 molar ratio = 10. Conversion of 6 was quantitative in all cases. Isolated yield based on starting 6. The reaction was carried out with 5
mol % of PdI2, with a KI:PdI2 molar ratio = 10.
conditions as those of Table 3, entries 1−7, was directly converted
into the corresponding bicyclic derivative, methyl 2-butyl-1-
hexanoyl-6,7-dihydro-5H-pyrrolizine-2-carboxylate 9, in 71%
yield (Scheme 4).
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with brine and dried over Na2SO4. The solvent was removed, and
the crude products were used as such for the next step.
Scheme 4. PdI2/KI-Catalyzed Synthesis of Methyl 2-Butyl-1-
hexanoyl-6,7-dihydro-5H-pyrrolizine-2-carboxylate 9 by
Oxidative Carbonylation of (S)-7-(pyrrolidin-2-yl)trideca-
5,8-diyn-7-ol 8
Second Step: Preparation of N-Boc-1-amino-3-yn-2-ols 3a and
3c−g. To a stirred suspension of Mg turnings (1.0 g, 41.1 mmol) in
anhydrous THF (6 mL), maintained under nitrogen and under reflux,
was added pure ethyl bromide (0.7 mL) to start the formation of the
Grignard reagent. The remaining bromide was added dropwise in
THF solution (2 mL of EtBr in 22 mL of THF; total amount of EtBr
added: 3.94 g, 36.2 mmol). The mixture was then allowed to reflux for
additional 20 min. After cooling, the resulting solution of EtMgBr was
transferred under nitrogen to a dropping funnel and added dropwise
under nitrogen to a solution of the 1-alkyne (36.2 mmol) (1-hexyne:
2.97 g; phenylacetylene: 3.69 g) in anhydrous THF (11 mL) at 0 °C with
stirring. After additional stirring at 0 °C for 15 min, the mixture was
allowed to warm up to room temperature, and then it was heated at
45 °C and stirred for 2 h. To the hot solution of 1-alkynylmagnesium
bromide thus obtained was added dropwise and under nitrogen a solution
of the crude N-Boc-2-amino aldehyde, obtained as described in the first
step, in anhydrous THF (13 mL). The resulting mixture was allowed to
stir at 35 °C overnight. Saturated NH4Cl (100 mL) and AcOEt (100 mL)
were sequentially added, the phases were separated, and the aqueous
phase was extracted with AcOEt (3 × 50 mL). The collected organic
layers were washed with brine and dried over Na2SO4. After filtration and
evaporation of the solvent, products were purified by column
chromatography on silica gel using 7:3 hexane−AcOEt (3a, 3d−g), 1:1
hexane−AcOEt (3c) as the eluent. With the exception of N-Boc-1-
aminooct-3-yn-2-ol 3c, all products were obtained as mixtures of syn and
anti diastereomers. In the case of N-Boc-3-amino-2-methyldec-5-yn-4-ol
3f, separation of the syn-3f and anti-3f diastereosiomers was possible using
hexane−AcOEt from 8:2 to 7:3 as eluent, to give pure syn-3f (936 mg,
18% based on starting N-Boc-D/L-valine methyl ester) and pure anti-3f
(672 mg, 13% based on starting N-Boc-D/L-valine methyl ester) together
with some fractions containing the mixture of the two diastereomers (1.01
g, 19% based on starting N-Boc-D/L-valine methyl ester).
N-Boc-2-amino-1-phenylnon-4-yn-3-ol (3a). (Mixture of diaster-
eomers A + B, A:B ratio = 1.6:1, determined by GLC). Yield: 2.4 g,
starting from 5.1 g of N-Boc-L-phenylalanine methyl ester (40%).
Colorless amorphous solid: IR (KBr) ν = 3379 (m), 2933 (m), 2230
(vw), 1675 (s), 1531 (m), 1391 (w), 1367 (m), 1250 (w), 1172 (m),
1041 (w), 759 (w), 705 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ =
7.32−7.16 [A (m, 5 H) + B (m, 5 H)], 4.92−4.79 [A (m, 1 H) + B
(m, 1 H)], 4.42−4.37 [B (m, br, 1 H)], 4.34 [A (dt, J = 4.5, 2.0, 1 H],
4.11−3.99 [B (m, 1 H)], 3.99−3.86 [A (m, 1 H)], 3.08−2.98 [A (m, 1
H) + B (m, 1 H)], 2.96−2.77 [A (m, 2 H) + B (m, 2 H)], 2.26 [A (td,
J = 7.0, 2.0, 2 H)], 2.20 [B (td, J = 7.0, 2.0, 2 H)], 1.60−1.25 [A (m, 4
H) + B (m, 4 H)], 1.38 [A (s, 9 H) + B (s, 9 H)], 0.94 [A (t, J = 7.2, 3
H)], 0.90 [B (t, J = 7.2, 3 H)]; 13C NMR (75 MHz, CDCl3) δ = 156.3
(A or B), 156.1 (B or A), 138.2 (A or B), 137.8 (B or A), 129.5 (A or
B), 129.3 (B or A), 128.53 (A or B), 128.48 (B or A), 126.6 (A or B),
126.4 (B or A), 87.8 (A or B), 86.9 (B or A), 79.9 (A or B), 79.6 (B or
A), 78.9 (A or B), 77.8 (B or A), 64.9 (A or B), 64.0 (B or A), 56.9 (A
or B), 56.7 (B or A), 37.6 (A or B), 37.1 (B or A), 30.8 (A or B), 30.7
(B or A), 28.3 (A + B), 22.04 (A or B), 21.98 (B or A), 18.5 (A or B),
18.4 (B or A), 13.6 (A + B); MS (ESI+, direct infusion) m/z = 354
[(M + Na)+]. Anal. calcd for C20H29NO3 (331.45): C, 72.47; H, 8.82;
N, 4.23. Found: C, 72.58; H, 8.83; N, 4.24.
CONCLUSIONS
■
In conclusion, we have developed a novel and general synthesis
of pyrrole-3-carboxylic ester derivatives 5 in good to high yields
(61−89%), starting from readily available building blocks, by a
simple two-step synthetic approach involving PdI2-catalyzed
oxidative carbonylation of N-Boc-1-amino-3-yn-2-ols 3 fol-
lowed by basic treatment. In the case of N-Boc-2-alkynyl-1-
amino-3-yn-2-ols 6, bearing an additional alkynyl substituent α
to the hydroxyl group, N-deprotection and water addition to
the triple bond occurred spontaneously under the carbon-
ylation conditions, thus allowing a direct synthesis of
multifunctionalized polysubstituted pyrroles (alkyl 4-acylpyr-
role-3-carboxylates 7) in one step in satisfactory yields (55−
75%). In a similar manner, (S)-7-(pyrrolidin-2-yl)trideca-5,8-
diyin-7-ol 8 was directly converted into the corresponding
bicyclic derivative, methyl 2-butyl-1-hexanoyl-6,7-dihydro-5H-
pyrrolizine-2-carboxylate 9, in 71% yield.
EXPERIMENTAL SECTION
■
General Experimental Methods. Melting points are uncorrected.
1H NMR and 13C NMR spectra were recorded at 25 °C in CDCl3
solutions at 300 or 500 MHz and 75 or 126 MHz, respectively, with
Me4Si as internal standard. Chemical shifts (δ) and coupling constants
(J) are given in ppm and in Hz, respectively. IR spectra were taken
with an FT-IR spectrometer. Mass spectra were obtained using a GC−
MS apparatus at 70 eV ionization voltage or a mass spectrometer
equipped with a turbo ion spray ionization source in the positive mode
[ion spray voltage (IS) 4500 V; curtain gas 10 psi; temperature 25 °C; ion
source gas (1) 20 psi; declustering and focusing potentials 50 and 400 V,
respectively]. All reactions were analyzed by TLC on silica gel 60 F254 or
on neutral alumina and by GLC using a gas chromatograph and capillary
columns with polymethylsilicone +5% phenylsilicone as the stationary
phase or using a gas chromatograph and a capillary column with diethyl
tert-butylsilyl-β-cyclodextrin as the stationary phase. Column chromatog-
raphy was performed on silica gel 60 (70−230 mesh). Evaporation refers
to the removal of solvent under reduced pressure.
Preparation of Substrates. Boc-protected α-alkynyl-β-amino
alcohols 3a−g, Boc-protected α,α′-dialkynyl-β-amino alcohols 6a−g,
and (S)-7-(pyrrolidin-2-yl)trideca-5,8-diyn-7-ol 8 were prepared as
described below. All other materials were commercially available and
were used without further purification.
N-Boc-1-aminooct-3-yn-2-ol (3c). Yield: 1.7 g, starting from 3.5 g
of N-Boc-glycine methyl ester (38%). Colorless oil: IR (film) ν = 3396
(m, br), 2965 (m), 2934 (m), 2236 (vw), 1695 (s), 1512 (s), 1367
(w), 1251 (m), 1171 (s), 1073 (m) cm−1; 1H NMR (300 MHz,
CDCl3) δ = 5.26−5.06 (m, br, 1 H), 4.41 (s, br, 1 H), 3.63−3.33 (m, 2
H), 3.32−3.16 (m, 1 H), 2.21 (td, J = 7.1, 2.0, 2 H), 1.55−1.33 (m, 4
H), 1.45 (s, 9 H), 0.91 (t, J = 7.2, 3 H); 13C NMR (75 MHz, CDCl3)
δ = 156.5, 86.4, 79.7, 78.9, 62.2, 47.1, 30.6, 28.4, 21.9, 18.4, 13.6; MS
(ESI+, direct infusion) m/z = 364 [(M + Na)+]. Anal. calcd for
C13H23NO3 (241.33): C, 64.70; H, 9.61; N, 5.80. Found: C, 64.60; H,
9.63; N, 5.81.
General Procedure for the Preparation of N-Boc-1-amino-3-
yn-2-ols 3a and 3c−g. First Step: Preparation of N-Boc-2-amino
Aldehydes. The method of Verkade11 was employed. To a cold
(−78 °C), mechanically stirred solution of methyl N-Boc-amino
esters (18.3 mmol) [N-Boc-
L-phenylalanine methyl ester: 5.1 g;
N-Boc- -alanine methyl ester: 3.7 g; N-Boc-D/L
L
-valine methyl
ester: 4.2 g; N-Boc-glycine methyl ester: 3.5 g] in CH2Cl2 (60 mL) was
added dropwise a 1.0 M solution of DIBAL-H in hexane (40 mL,
40 mmol) under nitrogen over 1 h. After additional stirring at −78
°C for 2 h, a 5 M solution of AcOH in benzene (34 mL) was
added dropwise at −78 °C. The resulting mixture was allowed to
warm to room temperature, and then it was poured into 10%
aqueous tartaric acid (100 mL) and extracted with hexane−AcOEt
(1:1) (3× 60 mL). The combined organic layers were washed
N-Boc-2-aminonon-4-yn-3-ol (3d). (Mixture of diastereomers A +
1
B, A:B ratio = 1.9:1, determined by H NMR). Yield: 2.6 g, starting
from 3.7 g of N-Boc-L-alanine methyl ester (56%). Colorless oil: IR
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(film) ν = 3404 (m, br), 2964 (m), 2934 (m), 2212 (w), 1695 (s),
1506 (m), 1455 (w), 1384 (m), 1367 (m), 1250 (w), 1169 (m), 1051
(m), 1029 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 4.94 [B (d, br,
J = 8.6, 1 H)], 4.86 [A (d, br, J = 9.1, 1 H)], 4.43−4.38 [B (m, 1 H)],
4.34 [A (dt, J = 5.1, 2.0, 1 H)], 3.93−3.73 [A (m, 1 H) + B (m, 1 H)],
3.61 [A (s, br, 1 H) + B (s, br, 1 H)], 2.26−2.17 [A (m, 2 H) + B (m,
2 H)], 1.55−1.32 [A (m, 4 H) + B (m, 4 H)], 1.45 [A (s, 9 H) + B (s,
9 H)], 1.22 [A (d, J = 6.9, 3 H)], 1.18 [B (d, J = 6.9, 3 H)], 0.91 [A (t,
J = 7.2, 3 H + B (t, J = 7.2, 3 H)]; 13C NMR (75 MHz, CDCl3) δ =
156.2 (B), 156.0 (A), 87.0 (B), 86.6 (A), 79.8 (B), 79.6 (A), 78.5 (A),
78.0 (B), 66.2 (B), 66.0 (A), 51.3 (B), 51.1 (A), 30.7 (A + B), 28.4
(A + B), 21.9 (A + B), 18.4 (A + B), 16.3 (A), 16.1 (B), 13.6 (A + B);
MS (ESI+, direct infusion) m/z = 278 [(M + Na)+]. Anal. calcd for
C14H25NO3 (255.35): C, 65.85; H, 9.87; N, 5.49. Found: C, 65.96; H,
9.84; N, 5.50.
N-Boc-4-amino-1-phenylpent-1-yn-3-ol (3e). (Mixture of diaster-
eoisomers A + B, A:B ratio = 1.6:1 by 1H NMR). Yield: 3.4 g, starting
from 3.7 g of N-Boc-L-alanine methyl ester (67%). Colorless oil: IR
(film) ν = 3353 (m, br), 2978 (m), 2932 (w), 2226 (vw), 1688 (s),
1504 (m), 1367 (m), 1249 (m), 1166 (m), 1047 (m), 757 (m), 691
(m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 7.47−7.41 [B (m, 5 H)],
7.34−7.27 [A (m, 5 H)], 4.86 [B (d, br, J = 9.0, 1 H)], 4.79 [A (d, br,
J = 8.1, 1 H)], 4.64 [B (d, br, J = 2.4, 1 H)], 4.57 [A (d, J = 5.3, 1 H)],
4.10−3.86 [A (m, 1 H) + B (m, 1 H)], 1.46 [B (s, 9 H)], 1.45 [A (s, 9
H)], 1.31 [A (d, J = 6.5, 3 H)], 1.27 [B (d, J = 6.9, 3 H)]; 13C NMR
(75 MHz, CDCl3) δ = 156.0 (A + B), 131.83 (A), 131.77 (B), 128.5
(B), 128.32 (A), 128.28 (A + B), 122.4 (A + B), 87.5 (A), 86.9 (B),
86.0 (A + B), 80.1 (B), 79.9 (A), 66.9 (B), 66.6 (A), 51.4 (B), 51.1
(A), 28.4 (A + B), 16.4 (A + B) (Note: the −OH signals were too broad
to be detected); MS (ESI+, direct infusion) m/z = 298 [(M + Na)+].
Anal. calcd for C16H21NO3 (275.34): C, 69.79; H, 7.69; N, 5.09.
Found: C, 69.85; H, 7.70; N, 5.08.
CDCl3) δ = 156.1 (A + B), 137.8 (A + B), 132.0 (B), 131.8 (A), 129.4
(A), 129.2 (B), 128.7 (B), 128.55 (A), 128.49 (A + B), 128.3 (B),
128.2 (A), 126.6 (B), 126.5 (A), 122.4 (A + B) 87.8 (A + B), 85.9
(A + B), 80.1 (A), 79.8 (B), 65.3 (B), 64.2 (A), 56.8 (B), 56.5 (A), 37.5
(A), 36.9 (B), 28.3 (A + B); MS (ESI+, direct infusion) m/z = 374
[(M + Na)+], 352 [(M + H)+]. Anal. calcd for C22H25NO3 (351.44):
C, 75.19; H, 7.17; N, 3.99. Found: C, 75.27; H, 7.15; N, 3.98.
Preparation of N-Boc-2-Amino-3-methyl-1-phenylnon-4-yn-
3-ol 3b. First Step: Preparation of (S)-N-Boc-3-amino-4-phenyl-2-
butanone. To a cold (−78 °C), mechanically stirred solution of
N-Boc-L-phenylalanine (4.0 g, 15.1 mmol) in anhydrous THF
(15 mL) was added dropwise a 1.6 M solution of methyllitium
in Et2O (30.2 mL, 48.3 mmol) under nitrogen over 0.5 h. The
reaction mixture was allowed to warm to room temperature,
stirred for additional 2 h, and then quenched with a 1 N
aqueous solution of HCl (66 mL). Et2O (50 mL) was added,
and the aqueous layer was separated and extracted with Et2O
(3 × 25 mL). The combined organic extracts were dried over
anhydrous Na2SO4. After filtration, the solvent was removed by
rotary evaporation. Purification by chromatography on silica gel
(1:1 hexane−AcOEt) gave (S)-N-Boc-3-amino-4-phenyl-2-
butanone as a colorless solid (mp 74−76 °C, lit.12 75−76
°C), whose spectroscopic data agreed with those reported in
the literature12 (yield: 2.58 g, 65% based on starting N-Boc-
L-
phenylalanine).
Second Step: Preparation of N-Boc-2-amino-3-methyl-1-phenyl-
non-4-yn-3-ol 3b. To a suspension of Mg turnings (0.4 g, 16.8 mmol)
in anhydrous THF (2 mL), maintained under nitrogen and under
reflux, was added pure ethyl bromide (0.2 mL) to start the formation
of the Grignard reagent. The remaining bromide was added dropwise
in THF solution (1 mL of EtBr in 9 mL of THF; total amount of EtBr
added: 1.9 g, 16.1 mmol). The mixture was then allowed to reflux for
additional 20 min. After cooling, the resulting solution of EtMgBr was
transferred under nitrogen to a dropping funnel and added dropwise under
nitrogen to a solution of 1-hexyne (1.3 g, 16.1 mmol) in anhydrous THF
(4 mL) at 0 °C with stirring. After additional stirring at 0 °C for 15 min, the
mixture was allowed to warm up to room temperature, and then it
was heated at 45 °C and stirred for 2 h. To the hot solution of the
1-hexynylmagnesium bromide thus obtained was added, dropwise and
under nitrogen, a solution of (S)-3-N-Boc-3-amino-4-phenyl-2-butanone
(obtained as described above, 2.13 g, 8.1 mmol) in anhydrous THF (5 mL).
The resulting mixture was allowed to stir at 35 °C overnight. Saturated
NH4Cl (50 mL) and AcOEt (50 mL) were sequentially added, the phases
were separated, and the aqueous phase was extracted with AcOEt (3 × 50
mL). The collected organic layers were washed with brine and dried over
Na2SO4. After filtration and evaporation of the solvent, N-Boc-2-amino-3-
methyl-1-phenylnon-4-yn-3-ol 3b (as a diastereomeric mixture A + B, A:B
ratio = 2.4:1, determined by GLC) was purified by column chromatography
on silica gel using 7:3 hexane−AcOEt as the eluent. Yield: 2.24 g, starting
from 2.13 g of (S)-N-Boc-3-amino-4-phenyl-2-butanone (80%). Colorless
amorphous solid: IR (KBr) ν = 3444 (m, br), 3377 (m), 2967 (m), 2933
(m), 2241 (vw), 1676 (s), 1530 (m), 1455 (w), 1366 (m), 1250 (m), 1171
syn-N-Boc-3-amino-2-methyldec-5-yn-4-ol (syn-3f). Yield: 934
mg, starting from 4.2 g of N-Boc-D/L-valine methyl ester (18%).
Colorless crystalline solid: mp 52−54 °C; IR (KBr) ν = 3403 (m, br),
2962 (m), 2933 (m), 2873 (w), 2230 (vw), 1696 (s), 1508 (m), 1390
1
(w), 1366 (w), 1248 (m), 1172 (m), 1047 (m), 1018 (w) cm−1; H
NMR (300 MHz, CDCl3) δ = 4.86 (d, br, J = 9.7, 1 H), 4.46−4.38 (m,
1 H), 3.49−3.36 (m, 1 H), 2.94 (d, br, J = 5.7, 1 H), 2.19 (td, J = 6.9,
2.0, 2 H), 2.11−1.98 (m, 1 H), 1.54−1.32 (m, 4 H), 1.45 (s, 9 H), 0.98
(d, J = 6.9, 3 H), 0.92 (d, J = 6.9, 3 H), 0.90 (t, J = 7.3, 3 H); 13C NMR
(75 MHz, CDCl3) δ = 156.9, 86.4, 79.4, 79.2, 63.9, 61.0, 30.6, 29.1,
28.4, 21.9, 20.2, 18.4, 18.1, 13.6; MS (ESI+, direct infusion) m/z = 306
[(M + Na)+]. Anal. calcd for C16H29NO3 (283.41): C 67.81, H 10.31,
N 4.94. Found: C 67.89, H, 10.28, N 4.93.
anti-N-Boc-3-amino-2-methyldec-5-yn-4-ol (anti-3f). Yield: 674
mg, starting from 4.2 g of N-Boc-D/L-valine methyl ester (13%).
Colorless crystalline solid: mp 42−44 °C; IR (KBr) ν = 3323 (m, br),
2962 (m), 2236 (v w), 1683 (s), 1541 (m), 1387 (m), 1366 (m), 1261
1
(m), 1176 (m), 1096 (m), 1028 (m), 802 (w) cm−1; H NMR (300
MHz, CDCl3) δ = 4.67 (d, br, J = 9.2, 1 H), 4.57−4.49 (m, 1 H), 3.53
(td, J = 9.2, 3.2, 1 H), 2.99 (d, br, J = 7.3, 1 H), 2.22 (td, J = 6.9, 1.6, 2
H), 1.82−1.66 (m, 1 H), 1.56−1.32 (m, 4 H), 1.46 (s, 9 H), 0.98 (d,
J = 6.9, 3 H), 0.97 (d, J = 6.9, 3 H), 0.91 (t, J = 7.3, 3 H); 13C NMR
(75 MHz, CDCl3) δ = 157.1, 87.2, 79.7, 77.7, 64.5, 61.2, 30.7, 28.4,
22.0, 19.9, 19.2, 18.4, 13.6; MS (ESI+, direct infusion) m/z = 306 [(M +
Na)+]. Anal. calcd for C16H29NO3 (283.41): C 67.81, H 10.31, N 4.94.
Found: C 67.89, H, 10.28, N 4.93.
1
(m), 753 (w), 700 (m) cm−1 ; H NMR (300 MHz, CDCl3) δ = 7.32−
7.13 [A (m, 5 H) + B (m, 5 H)], 4.64 [B (d, br, J = 9.7, 1 H)], 4.54 [A (d,
br, J = 8.9, 1 H)], 3.98−3.84 [A (m, 1 H) + B (m, 1 H)], 3.36−3.22 [A (m,
1 H) + B (m, 1 H)], 2.89 [A (s, br, 1 H)], 2.72 [B (s, br, 1 H)], 2.70−2.54
[A (m, 1 H) + B (m, 1 H)], 2.25 [B (t, J = 6.9, 2 H)], 2.24 [A (t, J = 6.9, 2
H)], 1.58−1.38 [A (m, 4 H) + B (m, 4 H)], 1.30 [A (s, 9 H)], 1.29 [B (s,
9 H)], 1.25 [A (s, 3 H) + B (s, 3 H)], 0.97−0.82 [A (m, 3 H) + B (m,
3 H)]; 13C NMR (75 MHz, CDCl3) δ = 156.1 (A + B), 138.6 (A + B),
129.3 (B), 129.2 (A), 128.3 (A + B), 126.3 (B), 126.2 (A), 85.6 (A + B),
81.9 (A + B), 79.5 (A + B), 71.4 (A), 70.8 (B), 60.3 (B), 60.0 (A), 37.4 (B),
36.7 (A), 30.8 (A + B), 29.7 (A + B), 28.2 (A + B), 22.0 (A + B), 18.4
(A + B), 13.6 (A + B); MS (ESI+, direct infusion) m/z = 368 [(M + Na)+],
346 [(M + H)+]. Anal. calcd for C21H31NO3 (345.48): C, 73.01; H, 9.04; N,
4.05. Found: C, 73.10; H, 9.01; N, 4.05.
N-Boc-2-amino-1,5-diphenylpent-4-yn-3-ol (3g). (Mixture of
1
diastereoisomers A + B, A:B ratio = 2:1, determined by H NMR).
Yield: 4.9 g, starting from 5.1 g of N-Boc-L-phenylalanine methyl ester
(76%). Colorless amorphous solid: IR (KBr) ν = 3444 (m, br), 3370
(m), 2978 (m), 2225 (vw), 1679 (s), 1527 (m), 1490 (w), 1444 (w),
1390 (w), 1367 (m), 1249 (m), 1171 (m), 1066 (m), 1041 (m), 756
1
(m), 704 (m); H NMR (300 MHz, CDCl3) δ = 7.49−7.45 [B (m, 2
H)], 7.44−7.39 [A (m, 2 H)], 7.35−7.15 [A (m, 8 H) + B (m, 8 H)],
5.05−4.82 [A (m, 1 H) + B (m, 1 H)], 4.68−4.62 [B (m, 1 H)], 4.59
[A (d, J = 4.4, 1 H)], 4.25−3.95 [A (m, 1 H) + B (m, 1 H)], 3.17−
2.75 [A (m, 2 H) + B (m, 2 H)], 1.38 [A (s, 9 H) + B (s, 9 H)] (Note:
the OH signal was too broad to be detected); 13C NMR (75 MHz,
General Procedure for the Preparation of N-Boc-2-alkynyl-
1-amino-3-yn-2-ols 6a−g. To a suspension of Mg turnings (0.6 g,
24.7 mmol) in anhydrous THF (3 mL), maintained under nitrogen
and under reflux, was added pure ethyl bromide (0.5 mL) to start the
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formation of the Grignard reagent. The remaining bromide was added
dropwise in THF solution (1.3 mL of EtBr in 12 mL of THF; total
amount of EtBr added: 2.63 g, 24.1 mmol). The mixture was then
allowed to reflux for additional 20 min. After cooling, the resulting
solution of EtMgBr was transferred under nitrogen to a dropping
funnel and added dropwise under nitrogen to a solution of the
1-alkyne (24.1 mmol) (1-hexyne: 1.98 g; phenylacetylene: 2.46 g; tert-
butylacetylene: 1.98) in anhydrous THF (6 mL) at 0 °C with stirring.
After additional stirring at 0 °C for 15 min, the mixture was allowed to
warm up to room temperature, and then it was heated at 45 °C and
stirred for 2 h. To the hot solution of the 1-alkynylmagnesium
bromide thus obtained was added, dropwise and under nitrogen, a
solution of the methyl Boc-protected-L-amino ester (6.21 mmol) (N-
Boc-L-alanine methyl ester: 1.26 g; N-Boc-L-leucine methyl ester:
1.52 g; N-Boc-D/L-phenylalanine methyl ester: 1.73 g ; N-Boc-D/L-valine
methyl ester: 1.44 g) in anhydrous THF (7 mL). The resulting mixture
was allowed to stir at 35 °C overnight. After cooling to room tem-
perature, saturated NH4Cl (50 mL) and AcOEt (50 mL) were
sequentially added, the phases were separated, and the aqueous phase
was extracted with AcOEt (3 × 50 mL). The collected organic layers
were washed with brine and dried over Na2SO4. After filtration and
evaporation of the solvent, products 6a−g were purified by column
chromatography on silica gel using 8:2 hexane−AcOEt as the eluent.
(S)-N-Boc-7-(1-aminoethyl)-trideca-5,8-diyn-7-ol (6a). Yield: 1.46
g, starting from 1.26 g of N-Boc-L-alanine methyl ester (70%). Yellow
(m, 1 H), 2.27−2.18 (m, 4 H), 1.57−1.33 (m, 8 H), 1.46 (s, 9 H), 1.00 (d,
J = 6.6, 3 H), 0.97 (d, J = 6.6, 3 H), 0.91 (t, J = 7.3, 3 H), 0.90 (t, J = 7.3,
3 H); 13C NMR (75 MHz, CDCl3) δ = 156.9, 85.6, 85.1, 79.9, 79.5, 79.4,
67.0, 63.4, 30.4, 29.2, 28.4, 22.2, 22.0, 18.5, 17.0, 13.6; MS (ESI+, direct
infusion) m/z = 386 [(M + Na)+]. Anal. calcd for C22H37NO3 (363.53):
C, 72.69; H, 10.26; N, 3.85. Found: C, 72.72; H, 10.25; N, 3.83.
(S)-N-Boc-3-(1-aminoethyl)-1,5-diphenylpenta-1,4-diyn-3-ol (6e).
Yield: 1.61 g, starting from 1.26 g of N-Boc-L-alanine methyl ester
(69%). Colorless amorphous solid: mp = 127−129 °C; [α]25
D
(MeOH, c = 9.0 × 10−3 g mL−1) −44°; IR (KBr) ν = 3308 (m,
br), 2230 (w), 1664 (s), 1537 (s), 1490 (m), 1456 (m), 1384 (m),
1315 (m), 1257 (w), 1159 (s), 1112 (m), 1009 (m), 856 (w), 756
(m), 692 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 7.51−7.43 (m,
4 H), 7.35−7.25 (m, 6 H), 4.97 (d, J = 9.3, 1 H), 4.34−4.20 (m, 1 H),
4.10 (s, 1 H), 1.47 (d, J = 6.9, 1 H), 1.44 (s, 9 H); 13C NMR (75 MHz,
CDCl3) δ = 156.3, 132.0, 128.8, 128.3, 128.2, 122.2, 87.8, 87.0, 84.9,
84.7, 80.1, 68.6, 55.8, 28.4, 17.1; MS (ESI+, direct infusion) m/z = 398
[(M + Na)+]. Anal. calcd for C24H25NO3 (375.46): C, 76.77; H, 6.71;
N, 3.73. Found: C, 76.81; H, 6.70; N, 3.71.
(S)-N-Boc-5-(1-aminoethyl)-2,2,8,8-tetramethylnona-3,6-diyn-5-
ol (6f). Yield: 1.48 g, starting from 1.26 g of N-Boc-L-alanine methyl
ester (71%). Colorless amorphous solid: mp = 63−66 °C; [α]25
D
(MeOH, c = 7.3 × 10−3 g mL−1) −44°; IR (KBr) ν = 3439 (m, br),
2972 (m), 2932 (w), 868 (w), 2247 (vw), 1675 (s), 1513 (m), 1455
(m), 1384 (s), 1267 (m), 1165 (m), 1054 (m), 979 (w), 858 (w) cm−1
;
oil: [α]25 (MeOH, c = 1.04 × 10−2 g mL−1) = −46°; IR (film) ν =
1H NMR (300 MHz, CDCl3) δ = 4.80−4.67 (m, 1 H), 4.03−3.88
(m, 1 H), 3.10 (s, br, 1 H), 1.46 (s, 9 H), 1.45 (d, J = 3.0, 3 H), 1.23 (s, 9
H), 1.22 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ = 156.0, 93.0, 92.8,
79.6, 78.2, 67.3, 55.6, 30.75, 30.66, 28.4, 27.4, 27.3, 17.2; MS (ESI+, direct
infusion) m/z = 358 [(M + Na)+]. Anal. calcd for C20H33NO3 (335.48):
C, 71.60; H, 9.91; N, 4.18. Found: C, 71.56; H, 9.90; N, 4.17.
D
3436 (m, br), 2960 (m), 2935 (m), 2874 (s), 2236 (w), 1701 (s),
1508 (s), 1507 (m), 1455 (m), 1367 (m), 1247 (m), 1165 (m), 1052
(m), 1019 (m), 861 (w), 756 (s) cm−1; 1H NMR (300 MHz, CDCl3)
δ = 4.76 (d, br, J = 6.8, 1 H), 4.04−3.87 (m, 1 H), 3.30 (s, br, 1 H),
2.24 (t, J = 7.0, 2 H), 2.23 (t, J = 7.0, 2 H), 1.57−1.34 (m, 8 H), 1.46
(s, 9 H), 1.31 (d, J = 6.8, 3 H), 0.915 (t, J = 7.1, 3 H), 0.906 (t, J = 7.1, 3
H); 13C NMR (75 MHz, CDCl3) δ = 156.1, 85.1, 84.9, 79.7, 79.6, 78.9,
67.5, 55.7, 30.6, 30.5, 28.4, 22.0, 18.4, 17.0, 13.5; MS (ESI+, direct
infusion) m/z = 358 [(M + Na)+]. Anal. calcd for C20H33NO3 (335.48):
C, 71.60; H, 9.91; N, 4.18. Found: C, 71.71; H, 9.89; N, 4.16.
N-Boc-7-(1-amino-2-phenylethyl)-trideca-5,8-diyn-7-ol (6b).
Yield: 1.76 g, starting from 1.73 g of N-Boc-D/L-phenylalanine methyl
ester (69%). Yellow amorphous solid: mp = 61−65 °C; IR (KBr) ν =
3380 (m), 3291 (m, br), 2959 (m), 2935 (m), 2873 (w), 2230 (w),
1687 (s), 1493 (w), 1453 (w), 1394 (m), 1366 (m), 1256 (w), 1170
(m), 1128 (m), 1061 (m), 1022 (w), 848 (w), 745 (m), 699 (m)
cm−1; 1H NMR (300 MHz, CDCl3) δ = 7.32−7.16 (m, 5 H), 4.70 (d,
J = 10.3, 1 H), 4.20−4.07 (m, 1 H), 3.52 (s, br, 1 H), 3.41 (dd, J = 13.9,
2.4, 1 H), 2.70 (dd, J = 13.9, 11.5, 1 H), 2.30−2.20 (m, 4 H), 1.60−1.35
(m, 8 H), 1.31 (s, 9 H,), 0.92 (t, J = 7.0), 0.91 (t, J = 7.0, 3 H); 13C NMR
(75 MHz, CDCl3) δ = 156.1, 138.3, 129.2, 128.3, 126.2, 85.50, 85.45,
79.6, 79.5, 78.8, 67.2, 60.9, 37.1, 30.5, 30.4, 28.2, 22.0, 18.4, 13.6; m/z =
434 [(M + Na)+]. Anal. calcd for C26H37NO3 (411.58): C, 75.87; H, 9.06;
N, 3.40. Found: C, 75.89; H, 9.04; N, 3.41.
(S)-N-Boc-5-(1-amino-3-methyl-butyl)-2,2,8,8-tetramethylnona-
3,6-diyn-5-ol (6g). Yield: 1.36 g, starting from 1.52 g of N-Boc-L-
leucine methyl ester (58%). Colorless amorphous solid: mp = 92−93
°C; [α]25D (MeOH, c = 8.5 × 10−3 g mL−1) −41°; IR (KBr) ν = 3449
(m, br), 2971 (m), 2930 (w), 2867 (w), 2244 (vw), 1701 (s), 1511
(m), 1367 (m), 1267 (w), 1175 (m), 1015 (w), 871 (w) cm−1; 1H NMR
(300 MHz, CDCl3) δ = 4.59 (d, J = 10.3, 1 H), 3.88 (t, br, J = 10.3, 1 H),
2.91 (s, br, 1 H), 1.74−1.62 (m, 2 H), 1.46 (s, 9 H), 1.42−1.30 (m, 1 H),
1.23 (s, 9 H), 1.22 (s, 9 H), 0.98−0.92 (m, 6 H); 13C NMR (75 MHz,
CDCl3) δ = 156.4, 93.0, 92.6, 79.5, 78.5, 77.4, 67.3, 58.3, 40.5, 30.75,
30.67, 28.4, 27.4, 27.3, 23.9, 21.7; MS (ESI+, direct infusion) m/z = 400
[(M + Na)+]. Anal. calcd for C23H39NO3 (377.56): C, 73.17; H, 10.41; N,
3.71. Found: C, 73.25; H, 10.40; N, 3.70.
Preparation of (S)-7-(Pyrrolidin-2-yl)trideca-5,8-diyn-7-ol
8. First Step: Preparation of L-Proline Methyl Ester. A solution
of L-proline methyl ester hydrochloride (3.64 g, 22 mmol) in
0.2 M aqueous NaOH solution (120 mL) was extracted with
diethyl ether (2 × 100 mL). The collected organic layers were
dried over Na2SO4. After filtration and evaporation of the
(S)-N-Boc-7-(1-amino-3-methylbutyl)-trideca-5,8-diyn-7-ol (6c).
Yield: 1.76 g, starting from 1.52 g of N-Boc-L-leucine methyl ester
(75%). Yellow oil: [α]25D (MeOH, c = 1.05 × 10−2 g mL−1) −55°; IR
(film) ν = 3379 (m, br), 2958 (m), 2234 (m), 2872 (w), 2223 (vw),
1716 (s), 1505 (m), 1436 (w), 1391 (w), 1367 (m), 1251 (w), 1166
(m), 1049 (w), 1025 (w) cm−1; 1H NMR (300 MHz, CDCl3) δ = 4.69
(d, br, J = 10.3, 1 H), 3.90 (t, br, J = 10.3, 1 H), 3.51 (s, br, 1 H),
2.27−2.18 (m, 4 H), 1.78−1.63 (m, 2 H), 1.58−1.33 (m, 9 H), 1.45
(s, 9 H), 1.00−0.88 (m, 12 H); 13C NMR (75 MHz, CDCl3) δ =
156.5, 85.0, 84.8, 79.9, 79.5, 79.0, 67.6, 58.2, 40.1, 30.54, 30.50, 28.4,
25.1, 23.9, 22.0, 18.5, 13.6; MS (ESI+, direct infusion) m/z = 400
[(M + Na)+]. Anal. calcd for C23H39NO3 (377.56): C, 73.17; H, 10.41;
N, 3.71. Found: C, 73.25; H, 10.39; N, 3.70.
solvent, the crude L-proline methyl ester thus obtained was
immediately used as such for the next step.
Second Step: Preparation of (S)-7-(Pyrrolidin-2-yl)trideca-5,8-
diyn-7-ol 8. To a suspension of Mg turnings (2.1 g, 86.4 mmol) in
anhydrous THF (9 mL), maintained under nitrogen and under reflux, was
added pure ethyl bromide (1.8 mL) to start the formation of the Grignard
reagent. The remaining bromide was added dropwise in THF solution
(4.5 mL of EtBr in 48 mL of THF; total amount of EtBr added: 9.2 g,
84.2 mmol). The mixture was then allowed to reflux for additional 20
min. After cooling, the resulting solution of EtMgBr was transferred under
nitrogen to a dropping funnel and added dropwise under nitrogen to a
solution of 1-hexyne (7.23 g, 88 mmol) in anhydrous THF (24 mL) at 0
°C with stirring. After additional stirring at 0 °C for 15 min, the mixture
was allowed to warm up to room temperature, and then it was heated at
45 °C and stirred for 2 h. To the hot solution of 1-hexynylmagnesium
bromide thus obtained was added, dropwise and under nitrogen, a
solution of crude L-proline methyl ester (obtained as described above) in
anhydrous THF (7 mL). The resulting mixture was allowed to stir at 35
°C overnight. After cooling to room temperature, saturated NH4Cl (100
mL) and AcOEt (100 mL) were sequentially added, the phases were
N-Boc-7-(1-amino-2-methylpropyl)-trideca-5,8-diyn-7-ol (6d).
Yield: 1.58 g, starting from 1.44 g of N-Boc-D/L-valine methyl ester
(70%). Yellow oil: IR (film) ν = 3440 (m, br), 2960 (m), 2930 (m),
2874 (m), 2234 (w), 1700 (s), 1505 (m), 1467 (w), 1392 (m), 1311
(m), 1239 (m), 1171 (m), 1094 (w), 1057 (m), 1000 (w), 872 (w),
1
761 (w) cm−1; H NMR (300 MHz, CDCl3) δ = 4.84 (d, br, J =
10.8, 1 H), 3.77 (dd, J = 10.8, 2.9, 1 H), 3.19 (s, br, 1 H), 2.46−2.32
4011
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separated, and the aqueous phase was extracted with AcOEt (3 × 50 mL).
The collected organic layers were washed with brine and dried over
Na2SO4. After filtration and evaporation of the solvent, (S)-7-(pyrrolidin-
2-yl)trideca-5,8-diyn-7-ol 8 was purified by column chromatography on
silica gel using 8:2 hexane−AcOEt as the eluent. Yield: 3.22 g, starting
30.8, 27.4, 26.4, 22.8, 13.9, 11.2; MS (ESI+, direct infusion) m/z = 408
[(M + Na)+], 386 [(M + H)+]. Anal. calcd for C23H31NO4 (385.50):
C 71.66, H 8.11, N 3.63. Found: C 71.70, H, 8.09, N 3.64.
Methyl N-Boc-2-butylpyrrole-3-carboxylate (4c). Yield: 82 mg
(44%, based on 0.66 mmol of starting 3c) (Table 2, entry 3). Colorless
oil: IR (film) ν = 2987 (w), 2923 (w), 1752 (s), 1699 (s), 1500 (w),
1423 (m), 1375 (m), 1340 (m), 1289 (m), 1230 (m), 1185 (m), 1095
(m), 846 (m), 782 (w), 754 (m), 700 (m) cm−1; 1H NMR (300 MHz,
CDCl3) δ = 7.12 (d, J = 3.6, 1 H), 6.49 (d, J = 3.6, 1 H), 3.81 (s, 3 H),
3.35−3.27 (m, 2 H), 1.64−1.50 (m, 2 H), 1.61 (s, 9 H), 1.49−1.34
(m, 2 H), 0.94 (t, J = 7.1, 3 H); 13C NMR (75 MHz, CDCl3) δ =
165.2, 148.8, 143.5, 120.3, 115.8, 110.9, 84.5, 51.0, 32.1, 27.9, 26.1,
22.7, 14.0; MS (ESI+, direct infusion) m/z = 304 [(M + Na)+], 386
[(M + H)+]. Anal. calcd for C15H23NO4 (281.35): C 64.03, H 8.24, N
4.98. Found: C 64.09, H, 8.27, N 4.97.
from 22 mmol of L-proline methyl ester (56%). Brown oil: [α]25
D
(MeOH, c = 1.05 × 10−2 g mL−1) −54°; IR (film) ν = 3436 (m, br),
2956 (m), 2930 (m), 2871 (w), 2345 (vw), 1648 (s), 1560 (w), 1522
1
(m), 1458 (m), 1430 (w), 1385 (m), 1299 (w) cm−1; H NMR (300
MHz, CDCl3) δ = 5.88 (s, 1 H), 3.77 (t, J = 7.1, 2H), 2.82 (t, J = 7.1, 2
H), 2.51−2.32 (m, 6 H), 1.60−1.29 (m, 10 H), 0.93 (t, J = 7.4, 3 H), 0.91
(t, J = 7.4, 3 H); GC−MS m/z = 261 (M+, 35), 218 (48), 205 (57), 191
(15), 190 (100), 163 (12), 162 (34), 148 (7), 120 (10), 119 (18). Anal.
calcd for C17H27NO (261.40): C, 78.11; H, 10.41; N, 5.36. Found: C,
78.12; H, 10.44, N, 5.33.
Methyl N-Boc-2-butyl-5-methylpyrrole-3-carboxylate (4d). Yield:
105 mg (54%, based on 0.66 mmol of starting 3d) (Table 2, entry 4).
Colorless amorphous solid: mp 34−36 °C; IR (KBr) ν = 2953 (m),
2931 (m), 1748 (s), 1712 (s), 1545 (m), 1466 (m), 1437 (m), 1396
(m), 1288 (m), 1217 (m), 1168 (m), 1128 (m), 1059 (m), 1000 (w),
783 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 6.23−6.20 (m, 1 H),
3.78 (s, 3 H), 3.25−3.17 (m, 2 H), 2.32 (d, J = 1.2, 3 H), 1.61 (s, 9 H),
1.60−1.48 (m, 2 H), 1.46−1.32 (m, 2 H), 0.93 (t, J = 7.3, 3 H); 13C
NMR (75 MHz, CDCl3) δ = 165.3, 149.8, 142.9, 130.0, 113.5, 110.7,
84.6, 51.0, 32.5, 27.9, 26.4, 22.8, 15.7, 14.0; MS (ESI+, direct infusion)
m/z = 318 [(M + Na)+]. Anal. calcd for C16H25NO4 (295.37): C
65.06, H 8.53, N 4.74. Found: C 65.17, H, 8.55, N 4.73.
Methyl N-Boc-5-methyl-2-phenylpyrrole-3-carboxylate (4e).
Yield: 98 mg (47%, based on 0.66 mmol of starting 3e) (Table 2,
entry 5). Colorless amorphous solid: mp 112−114 °C; IR (KBr) ν =
2969 (m), 1742 (s), 1721 (s), 1544 (m), 1433 (w), 1371 (m), 1346
(m), 1283 (m), 1237 (m), 1178 (m), 1153 (m), 1091 (m), 782 (m),
725 (m), 699 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 7.42−7.28
(m, 5 H), 6.37 (q, J = 1.0, 1 H), 3.63 (s, 3 H), 2.42 (d, J = 1.0, 3 H),
1.67 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ = 164.5, 149.6, 138.1,
133.7, 131.6, 130.0, 127.9, 127.5, 115.3, 110.7, 84.5, 51.0, 27.2, 14.7;
MS (ESI+, direct infusion) m/z = 316 [(M + H)+]. Anal. calcd for
C18H21NO4 (315.36): C 68.55, H 6.71, N 4.44. Found: C 68.47, H,
6.72, N 4.43.
General Procedure for the Synthesis of N-Protected Pyrrole-
3-carboxylic Esters 4a−g and N-Unsubstituted Pyrrole-3-
carboxylic Esters 5a−g. A 250 mL stainless steel autoclave was
charged in the presence of air with PdI2 (9.5 mg, 2.64 × 10−2 mmol or
23.7 mg, 6.58 × 10−2 mmol, see Table 2), KI (43.8 mg, 0.26 mmol or
109.2 mg, 0.66 mmol, see Table 2), anhydrous ROH (R = Me or Et,
6.6 mL), and N-Boc-1-amino-3-yn-2-ols (1.32 mmol) (N-Boc-2-
amino-1-phenylnon-4-yn-3-ol 3a: 437 mg; N-Boc-2-amino-3-methyl-1-
phenylnon-4-yn-3-ol 3b: 456 mg; N-Boc-1-aminooct-3-yn-2-ol 3c: 318
mg; N-Boc-2-aminonon-4-yn-3-ol 3d: 337 mg; N-Boc-4-amino-1-
phenylpent-1-yn-3-ol 3e: 363 mg; N-Boc-3-amino-2-methyl-dec-5-yn-
4-ol 3f: 374 mg; N-Boc-2-amino-1,5-diphenylpent-4-yn-3-ol 3g: 464
mg). The autoclave was sealed, and while the mixture was stirred, the
autoclave was pressurized with CO (16 atm) and air (up to 20 atm).
After being stirred at 80 °C for 3 h (3a−c) or 100 °C for 2 h (3d−g),
the autoclave was cooled, degassed and opened. The mixture was
diluted with ROH (R = Me or Et) in a volumetric flask (50 mL) to a
total volume of 50 mL. Evaporation of 25 mL of this solution (formally
deriving from 0.66 mmol of substrate) followed by column
chromatography on silica gel (95:5 to 9:1 hexane−AcOEt as eluent)
afforded pure products 4 and 5 (the order of elution was 5a, 4a and
4b−g, 5b−g). To the remaining 25 mL was added ROH (2 mL) and a
6.5 N solution of NaOR in ROH (0.80 mL, 5.2 mmol, for products
deriving from 3a−e and 3g; 3.15 mL, 20.5 mmol, for products deriving
from 3f). The mixture was allowed to stir in a Schlenk flask at 60 °C
for 8 h (for products deriving from 3a, 3b, 3g), 25 °C for 15 h (for
products deriving from 3c, 3d, 3e), or 25 °C for 72 h (for products
deriving from 3f). Three-fourths of the initial solvent volume were
evaporated, and the mixture was diluted with 10 mL of Et2O and
10 mL of water. The phases were separated, and the organic layer was
dried over Na2SO4. After filtration and elimination of the solvent by
rotary evaporation, crude products 5a−g were purified by column
chromatography on silica gel using 9:1 hexane−AcOEt as eluent.
Methyl N-Boc-5-benzyl-2-butylpyrrole-3-carboxylate (4a). Yield:
10 mg (4%, based on 0.66 mmol of starting 3a) (Table 2, entry 1).
Yellow oil: IR (film) ν = 2955 (m), 2871 (w), 1751 (s), 1710 (s), 1541
(m), 1454 (m), 1370 (m), 1303 (m), 1213 (m), 1127 (m), 1055 (m),
Methyl N-Boc-2-butyl-5-isopropylpyrrole-3-carboxylate (4f).
Yield: 66 mg (31%, based on 0.66 mmol of starting 3f) (Table 2,
entry 7). Colorless oil: IR (film) ν = 2957 (m), 2919 (m), 1750 (s),
1712 (s), 1547 (m), 1437 (m), 1395 (m), 1370 (m), 1304 (m), 1216
1
(m), 1149 (m), 1061 (m), 1003 (w), 850 (w), 783 (m) cm−1; H
NMR (300 MHz, CDCl3) δ = 6.27 (d, J = 0.8, 1 H), 3.79 (s, 3 H),
3.28 (heptuplet of doublets, J = 6.7, 0.8, 1 H), 3.20−3.11 (m, 2 H),
1.62 (s, 9 H), 1.60−1.47 (m, 2 H), 1.45−1.31 (m, 2 H), 1.20 (d, J =
6.7, 6 H), 0.92 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ =
165.4, 150.1, 142.4, 140.9, 112.9, 107.0, 84.9, 50.9, 32.4, 27.8, 26.4,
26.2, 22.9, 13.9; MS (ESI+, direct infusion) m/z = 324 [(M + H)+].
Anal. calcd for C18H29NO4 (323.43): C 66.84, H 9.04, N 4.33. Found:
C 66.77, H, 9.06, N 4.33.
Ethyl N-Boc-5-benzyl-2-phenylpyrrole-3-carboxylate (4g). Yield:
142 mg (53%, based on 0.66 mmol of starting 3g) (Table 2, entry 10).
Colorless amorphous solid: mp 74−76 °C; IR (KBr) ν = 2957 (m),
2936 (m), 2873 (w), 1754 (s), 1717 (s), 1570 (w), 1508 (w), 1438
(m), 1371 (m), 1293 (m), 1269 (m), 1205 (m), 1161 (m), 1103 (m),
1002 (m), 849 (m), 737 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ =
7.39−7.16 (m, 10 H), 6.35 (s, 1 H), 4.19 (s, 2 H), 4.07 (q, J = 7.2,
2 H), 1.09 (t, J = 7.2, 3 H), 1.0 (s, 9 H); 13C NMR (75 MHz, CDCl3)
δ = 164.2, 149.4, 138.7, 138.4, 134.1, 133.4, 130.0, 128.9, 128.4, 127.9,
127.4, 126.3, 115.4, 111.7, 84.5, 59.7, 34.2, 26.9, 14.0; MS (ESI+,
direct infusion) m/z = 428 [(M + Na)+]. Anal. calcd for C25H27NO4
(405.49): C 74.05, H 6.71, N 3.45. Found: C 74.15, H, 6.72, N 3.46.
Methyl 5-Benzyl-2-butyl-1H-pyrrole-3-carboxylate (5a). Yield:
122 mg (68% based on 0.66 mmol of starting 3a) (Table 2, entry
1). Colorless oil: IR (film) ν = 3312 (m, br), 2956 (m), 2930 (m),
1677 (s), 1524 (w), 1495 (w), 1456 (m), 1367 (m), 1224 (m), 1096
(m), 1075 (m), 782 (m), 701 (m) cm−1; 1H NMR (300 MHz, CDCl3)
δ = 8.17 (s, br, 1 H), 7.34−7.11 (m, 5 H), 6.27 (d, J = 2.7, 1 H), 3.87
1
848 (m), 784 (m), 701 (m) cm−1; H NMR (300 MHz, CDCl3) δ =
7.31−7.13 (m, 3 H), 7.13−7.04 (m, 2 H), 6.17 (s, 1 H), 4.11 (s, 2 H),
3.76 (s, 3 H), 3.27−3.16 (m, 2 H), 1.64−1.48 (m, 2 H), 1.48−1.31
(m, 2 H), 1.41 (s, 9 H), 0.93 (t, J = 7.2, 3 H); 13C NMR (75 MHz,
CDCl3) δ = 165.2, 149.7, 143.3, 139.3, 132.5, 128.6, 128.4, 126.3,
113.6, 112.2, 84.9, 50.8, 34.9, 32.5, 27.6, 26.3, 22.8, 13.9; MS (ESI+,
direct infusion) m/z = 394 [(M + Na)+]. Anal. calcd for C22H29NO4
(371.47): C 71.13, H 7.87, N 3.77. Found: C 71.18, H, 7.87, N 3.78.
Methyl N-Boc-5-benzyl-2-butyl-4-methylpyrrole-3-carboxylate
(4b). Yield: 181 mg (71%, based on 0.66 mmol of starting 3b)
(Table 2, entry 2). Colorless oil: IR (film) ν = 2956 (m), 1748 (s),
1707 (s), 1604 (w), 1533 (w), 1437 (m), 1383 (m), 1300 (m), 1250
(m), 1133 (s), 1105 (m), 844 (w), 758 (m), 704 (w) cm−1; 1H NMR
(300 MHz, CDCl3) δ = 7.27−7.19 (m, 2 H), 7.17−7.10 (m, 1 H),
7.02−6.95 (m, 2 H), 4.15 (s, 2 H), 3.83 (s, 3 H), 3.16−3.08 (m, 2 H),
2.18 (s, 3 H), 1.59−1.47 (m, 2 H), 1.45−1.31 (m, 2 H), 1.30 (s, 9 H),
0.92 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ = 166.3, 149.7,
142.1, 139.9, 128.3, 127.8, 127.5, 125.9, 119.7, 113.8, 84.6, 50.8, 32.5,
4012
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(s, 2 H), 3.73 (s, 3 H), 2.85 (t, J = 7.7, 2 H), 1.61−1.46 (m, 2 H),
1.38−1.24 (m, 2 H), 0.88 (t, J = 7.2, 3 H); 13C NMR (75 MHz,
CDCl3) δ = 166.0, 140.0, 139.0, 128.69, 128.68, 128.64, 126.6, 110.9,
108.5, 50.5, 33.8, 31.7, 27.0, 22.5, 13.8; GC−MS m/z = 271 (M+, 27),
240 (7), 228 (100), 212 (11), 196 (8), 169 (13), 141 (4), 120 (7), 105
(8), 91 (31), 78 (8), 65 (10). Anal. calcd for C17H21NO2 (271.35): C
75.25, H 7.80, N 5.16. Found: C 75.19, H, 7.82, N 5.15.
Anal. calcd for C13H21NO2 (223.16): C 69.92, H 9.48, N 6.27. Found:
C 69.87, H, 9.46, N 6.28.
Ethyl 5-Benzyl-2-phenyl-1H-pyrrole-3-carboxylate (5g). Yield:
131 mg (65% based on 0.66 mmol of starting 3g) (Table 2, entry
10). Colorless amorphous solid: mp 95−97 °C; IR (KBr) ν = 3298
(m), 1662 (s), 1482 (m), 1438 (m), 1385 (m), 1284 (w), 1263 (m),
1227 (m), 1179 (m), 1107 (m), 1019 (w), 766 (s), 698 (m) cm−1; 1H
NMR (300 MHz, CDCl3) δ = 8.71 (s, br, 1 H), 7.48−7.40 (m, 2 H),
7.30−7.12 (m, 8 H), 6.41−6.37 (m, 1 H), 4.06 (q, J = 7.2, 2 H), 3.84
(s, 2 H), 1.15 (t, J = 7.2, 3 H); 13C NMR (75 MHz, CDCl3) δ = 165.3,
138.8, 136.7, 132.2, 131.1, 128.9, 128.6, 127.9, 127.8, 126.5, 111.8,
110.0, 59.6, 33.6, 14.2; GC−MS m/z = 305 (M+, 100), 276 (19), 260
(38), 232 (56), 230 (17), 228 (12), 200 (11), 182 (20), 170 (4), 154
(8), 127 (9), 115 (11), 91 (20), 77 (10). Anal. calcd for C20H19NO2
(305.37): C 78.66, H 6.27, N 4.59. Found: C 78.78, H, 6.26, N 4.60.
General Procedure for the Synthesis of Pyrrole-3-carboxylic
Esters 7a−g and 9. A 35 mL stainless steel autoclave was charged in
the presence of air with PdI2 (5.0 mg, 1.39 × 10−2 mmol), KI (23 mg,
13.9 × 10−2 mmol) and a solution of 6 (0.69 mmol) [(S)-N-Boc-7-(1-
aminoethyl)-trideca-5,8-diyn-7-ol 6a: 232 mg; N-Boc-7-(1-amino-2-
phenylethyl)-trideca-5,8-diyn-7-ol 6b: 285 mg; (S)-N-Boc-7-(1-amino-
3-methylbutyl)-trideca-5,8-diyn-7-ol 6c: 261 mg; N-Boc-7-(1-amino-2-
methylpropyl)-trideca-5,8-diyn-7-ol 6d: 252 mg; (S)-N-Boc-3-(1-
aminoethyl)-1,5-diphenylpenta-1,4-diyn-3-ol 6e: 260 mg; (S)-N-Boc-
5-(1-aminoethyl)-2,2,8,8-tetramethylnona-3,6-diyn-5-ol 6f: 232 mg;
(S)-N-Boc-5-(1-amino-3-methyl-butyl)-2,2,8,8-tetramethylnona-3,6-
diyn-5-ol 6g: 261 mg; (S)-7-(pyrrolidin-2-yl)trideca-5,8-diyn-7-ol 8:
181 mg] in ROH (R = Me or Et, 3.5 mL). The autoclave was sealed,
and while the mixture was stirred, the autoclave was pressurized with
CO (16 atm) and air (up to 20 atm). After being stirred at 100 °C for
15 h, the autoclave was cooled, degassed, and opened. The solvent was
evaporated, and the products were purified by column chromatog-
raphy on silica gel: 7a was a yellow oil (8:2 hexane−AcOEt, 142 mg,
70% based on 6a); 7a′ was a colorless oil (8:2 hexane−AcOEt, 117 mg,
55% based on 6a); 7b was a colorless oil (8:2 hexane−AcOEt, 186 mg,
73% based on 6b); 7c was a yellow oil (8:2 hexane−AcOEt, 173 mg,
75% based on 6c); 7d was a yellow solid, mp 27−28 °C (8:2 hexane−
AcOEt, 150 mg, 68% based on 6d); 7e was a yellow oil (8:2 hexane−
AcOEt, 129 mg, 56% based on 6e); 7f was a colorless oil (8:2 hexane−
AcOEt, 134 mg, 66% based on 6f); 7g was a yellow oil (7:3 hexane−
AcOEt, 162 mg, 70% based on 6g); 9 was a yellow oil (8:2 hexane−
AcOEt, 156 mg, 71% based on 8).
Methyl 5-Benzyl-2-butyl-4-methyl-1H-pyrrole-3-carboxylate (5b).
Yield: 167 mg (89%, based on 0.66 mmol of starting 3b) (Table 2,
entry 2). Colorless amorphous solid: mp 80−82 °C; IR (KBr) ν =
3289 (m, br), 2956 (m), 2929 (m), 1659 (s), 1470 (m), 1455 (m),
1364 (w), 1260 (m), 1121 (m), 1082 (m), 1029 (m), 756 (w), 702
1
(w) cm−1; H NMR (300 MHz, CDCl3) δ = 7.81 (s, br, 1 H), 7.33−
7.16 (m, 3 H), 7.16−7.09 (m, 2 H), 3.86 (s, 2 H), 3.77 (s, 3 H), 2.86−
2.77 (m, 2 H), 2.22 (s, 3 H), 1.58−1.45 (m, 2 H), 1.39−1.23 (m, 2 H),
0.88 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ = 166.7, 139.4,
128.7, 128.4, 126.4, 124.8, 117.1, 110.2, 50.3, 31.8, 31.4, 27.6, 22.5,
13.8, 11.1; GC−MS m/z = 285 (M+, 36), 270 (2), 254 (7), 243 (18),
242 (100), 226 (6), 210 (3), 183 (4), 167 (3), 107 (2), 91 (8). Anal.
calcd for C18H23NO2 (285.38): C 75.76, H 8.12, N 4.91. Found: C
75.70, H, 8.10, N 4.92.
Methyl 2-Butyl-1H-pyrrole-3-carboxylate (5c). Yield: 73 mg (61%
based on 0.66 mmol of starting 3c) (Table 2, entry 3). Colorless oil:
IR (film) ν = 3356 (m, br), 2956 (m), 1678 (s), 1574 (m), 1466 (m),
1340 (m), 1264 (m), 1199 (m), 1129 (m), 1041 (m), 899 (m), 722
1
(m) cm−1; H NMR (300 MHz, CDCl3) δ = 8.78 (s, br, 1 H), 6.58−
6.53 (m, 2 H), 3.80 (s, 3 H), 2.98−2.91 (m, 2 H), 1.68−1.55 (m, 2 H),
1.43−1.28 (m, 2 H), 0.91 (t, J = 7.3, 3 H); 13C NMR (75 MHz,
CDCl3) δ = 165.9, 140.1, 115.7, 111.1, 110.6, 50.7, 31.5, 27.0, 22.5,
13.9; GC−MS m/z = 181 (M+, 27), 166 (4), 150 (19), 139 (31), 138
(100), 124 (25), 120 (41), 108 (49), 106 (89), 93 (14), 80 (49), 79
(39), 78 (19), 65 (11). Anal. calcd for C10H15NO2 (181.23): C 66.27,
H 8.34, N 7.73. Found: C 66.39, H, 8.32, N 7.72.
Methyl 2-Butyl-5-methyl-1H-pyrrole-3-carboxylate (5d). Yield: 90
mg (70% based on 0.66 mmol of starting 3d) (Table 2, entry 4).
Colorless oil: IR (film) ν = 3319 (m, br), 2955 (m), 2930 (m), 2872
(w), 1676 (s), 1601 (w), 1530 (w), 1460 (m), 1400 (w), 1367 (w),
1224 (m), 1097 (m), 1075 (m), 781 (m), cm−1; 1H NMR (300 MHz,
CDCl3) δ = 8.11 (s, br, 1 H), 6.20−6.16 (m, 1 H), 3.77 (s, 3 H),
2.93−2.85 (m, 2 H), 2.20 (s, 3 H), 1.65−1.53 (m, 2 H), 1.43−1.29
(m, 2 H), 0.92 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ =
166.1, 139.3, 125.6, 110.8, 107.5, 50.6, 31.8, 26.9, 22.5, 13.9, 12.7;
GC−MS m/z = 195 (M+, 31), 180 (2), 164 (9), 152 (100), 138 (7),
134 (7), 122 (10), 120 (19), 106 (3), 94 (7), 93 (8). Anal. calcd for
C11H17NO2 (195.26): C 67.66, H 8.78, N 7.17. Found: C 67.60, H,
8.80, N 7.15.
Methyl 5-Methyl-2-phenyl-1H-pyrrole-3-carboxylate (5e). Yield:
113 mg (80% based on 0.66 mmol of starting 3e) (Table 2, entry 5).
Yellow oil: IR (film) ν = 3309 (m, br), 2948 (m), 1681 (s), 1593 (m),
1467 (m), 1333 (w), 1283 (m), 1233 (m), 1167 (m), 1117 (m), 943
(m), 782 (m), 696 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 8.49
(s, br, 1 H), 7.58−7.49 (m, 2 H), 7.40−7.27 (m, 3 H), 6.37−6.33 (m,
1 H), 3.68 (s, 3 H), 2.22 (d, J = 1.0, 3 H); 13C NMR (75 MHz,
CDCl3) δ = 165.6, 136.2, 132.3, 128.8, 128.1, 127.9, 127.8, 111.7,
109.6, 50.8, 12.6; GC−MS m/z = 215 (M+, 78), 199 (4), 184 (100),
170 (3), 156 (13), 141 (4), 128 (13), 115 (7), 104 (7), 92 (7), 77
(17), 63 (8). Anal. calcd for C13H13NO2 (215.25): C 72.54, H 6.09, N
6.51. Found: C 72.70, H, 6.10, N 6.50.
Methyl 2-Butyl-4-hexanoyl-5-methyl-1H-pyrrole-3-carboxylate
(7a). Yield: 142 mg, starting from 232 mg of (S)-N-Boc-7-(1-
aminoethyl)-trideca-5,8-diyn-7-ol 6a (70%) (Table 3, entry 1). Yellow
oil: IR (film) ν = 3289 (s), 2957 (w), 2928 (m), 2872 (m), 1705 (s),
1646 (m), 1528 (m), 1448 (m), 1169 (m), 1110 (m), 1072 (m), 787
1
(w), 736 (w) cm−1; H NMR (300 MHz, CDCl3) δ = 9.28 (s, br, 1
H), 3.78 (s, 3 H), 2.77 (t, J = 7.7, 2 H), 2.70 (t, J = 7.7, 2 H), 2.17 (s, 3
H), 1.71−1.48 (m, 4 H), 1.40−1.20 (m, 6 H), 0.89 (t, J = 7.3, 3 H),
0.87 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ = 202.9, 165.8,
138.7, 129.9, 123.3, 110.5, 51.0, 43.5, 31.8, 31.7, 26.6, 24.7, 22.5, 22.4,
13.9, 13.8, 12.1; GC−MS m/z = 293 (M+, 10), 278 (3), 262 (6), 261
(7), 250 (6), 232 (11), 223 (12), 222 (100), 218 (16), 205 (26), 192
(13), 176 (7), 163 (10), 162 (9), 134 (7), 121 (11), 107 (9), 93 (30).
Anal. calcd for C17H27NO3 (293.40): C, 69.59; H, 9.28; N, 4.77.
Found: C, 69.65; H, 9.30; N, 4.76.
Ethyl 2-Butyl-4-hexanoyl-5-methyl-1H-pyrrole-3-carboxylate
(7a′). Yield: 117 mg, starting from 232 mg of (S)-N-Boc-7-(1-
aminoethyl)-trideca-5,8-diyn-7-ol 6a (55%) (Table 3, entry 8). Yellow
oil: IR (film) ν = 3300 (s), 2957 (m), 2927 (m), 2872 (w), 1709 (s),
1652 (s), 1525 (m), 1435 (m), 1174 (m), 1108 (m), 1070 (m) cm−1;
δ = 8.93 (s, br, 1 H), 4.26 (q, J = 7.3, 2 H), 2.79 (t, J = 7.7, 2 H), 2.73
(t, J = 7.7, 2 H), 2.20 (s, 3 H), 1.70−1.50 (m, 4 H), 1.40−1.20 (m, 6
H), 1.32 (t, J = 7.3, 3 H), 0.96−0.82 (m, 6 H); 13C NMR (75 MHz,
CDCl3) δ = 203.1, 165.4, 138.5, 129.9, 123.0, 110.5, 60.0, 43.6, 31.8,
31.6, 26.7, 24.7, 22.55, 22.46, 14.3, 14.0, 13.8, 12.2; GC−MS m/z =
307 (M+, 28), 292 (6), 264 (14), 262 (18), 261 (21), 251 (11), 236
(100), 232 (31), 218 (33), 208 (98), 205 (45), 192 (13), 190 (10),
163 (21), 148 (6), 134 (10), 120 (8), 107 (10), 93 (26). Anal. calcd
Methyl 2-Butyl-5-isopropyl-1H-pyrrole-3-carboxylate (5f). Yield:
116 mg (79% based on 0.66 mmol of starting 3f) (Table 2, entry 7).
Colorless oil: IR (film) ν = 3333 (m, br), 2959 (m), 2932 (m), 2871
(w), 1671 (s), 1523 (w), 1457 (m), 1384 (w), 1285 (w), 1200 (w),
1
1113 (m), 757 (m) cm−1; H NMR (300 MHz, CDCl3) δ = 8.03 (s,
br, 1 H), 6.22 (dd, J = 3.0, 1.0, 1 H), 3.78 (s, 3 H), 2.95−2.87 (m, 2
H), 2.83 (heptuplet of doublets, J = 6.9, 1.0, 1 H), 1.67−1.54 (m, 2
H), 1.44−1.30 (m, 2 H), 1.23 (d, J = 6.9, 6 H), 0.92 (t, J = 7.3, 3 H);
13C NMR (75 MHz, CDCl3) δ = 166.0, 139.1, 136.9, 110.3, 104.6,
50.6, 31.7, 27.0, 26.8, 22.6, 22.4, 13.9; GC−MS m/z = 223 (M+, 40),
208 (70), 192 (11), 180 (100), 164 (14), 148 (7), 120 (8), 107 (18).
4013
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Article
for C18H29NO3 (307.43): C, 70.32; H, 9.51; N, 4.56. Found: C, 70.44;
H, 9.49, N, 4.57.
(s, 3 H), 1.34 (s, 9 H), 1.00 (s, 9 H); 13C NMR (126 MHz, CDCl3)
δ = 198.9, 168.5, 140.2, 129.3, 124.2, 111.3, 54.1, 51.7, 32.5, 31.5, 29.9,
29.6, 13.3; GC−MS m/z = 293 (M+, 14), 278 (2), 261 (8), 246 (26),
222 (100), 205 (42), 190 (58), 172 (9), 121 (20). Anal. calcd for
C17H27NO3 (293.40): C, 69.59; H, 9.28; N, 4.77. Found: C, 69.65; H,
9.30; N, 4.76.
Methyl 2-tert-Butyl-4-(3,3-dimethylbutanoyl)-5-isobutyl-1H-pyr-
role-3-carboxylate (7g). Yield: 162 mg, starting from 261 mg of
(S)-N-Boc-5-(1-amino-3-methyl-butyl)-2,2,8,8-tetramethylnona-3,6-
diyn-5-ol 6g (70%) (Table 3, entry 7). Yellow amorphous solid: mp
127−129 °C; IR (KBr) ν = 3369 (m, br), 2963 (m), 1712 (s), 1652
(s), 1513 (w), 1438 (m), 1366 (m), 1271 (w), 1222 (m), 1168 (m),
1062 (m), 710 (w) cm−1; 1H NMR (300 MHz, CDCl3) δ = 7.99 (s, br,
1 H), 3.80 (s, 3 H), 2.56 (d, J = 7.3, 2 H), 2.50 (s, 2 H), 2.02−1.82
(m, 1 H), 1.37 (s, 9 H), 1.01 (s, 9 H); 0.93 (d, J = 6.6, 6 H); 13C NMR
(75 MHz, CDCl3) δ = 199.1, 167.8, 140.5, 131.9, 124.9, 111.1, 54.5, 51.6,
35.9, 31.4, 29.9, 29.5, 29.4, 22.5; GC−MS m/z = 335 (M+, 28), 304 (15),
303 (44), 288 (43), 274 (10), 264 (83), 247 (37), 246 (100), 236 (28),
232 (36), 204 (9), 120 (10). Anal. calcd for C20H33NO3 (335.48): C,
71.60; H, 9.91; N, 4.18. Found: C, 71.67; H, 9.90; N, 4.20.
Methyl 2-Butyl-1-hexanoyl-6,7-dihydro-5H-pyrrolizine-2-carbox-
ylate (9). Yield: 156 mg, starting from 181 mg of (S)-7-pyrrolidin-2-yl-
trideca-5,8-diyn-7-ol 8 (71%) (Scheme 4). Yellow amorphous solid:
mp = 59−62 °C; IR (KBr) ν = 3447 (m, br), 2983 (w), 2928 (w),
1744 (s), 1384 (s), 1327 (s), 1291 (w), 1153 (m), 1136 (m), 756 (m),
691 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 3.89 (t, J = 7.3, 2 H),
3.80 (s, 3 H), 3.02 (t, J = 7.4, 2 H), 2.76−2.66 (m, 4 H), 2.58−2.46 (m,
2 H), 1.69−1.25 (m, 10 H), 1.00−0.83 (m, 6 H); 13C NMR (75 MHz,
CDCl3) δ = 197.8, 166.1, 141.6, 134.9, 117.3, 114.4, 51.2, 45.1, 41.7,
31.76, 31.72, 26.5, 26.0, 25.7, 24.4, 22.6, 22.4, 14.0, 13.8; GC−MS m/z =
319 (M+, 19), 288 (11), 287 (13), 276 (14), 263 (18), 258 (14), 258
(14), 249 (16), 248 (100), 231 (17), 218 (10), 189 (26), 178 (8), 160
(11), 147 (9), 119 (28), 91 (11). Anal. calcd for C19H29NO3 (319.44): C,
71.44; H, 9.15; N, 4.38. Found: C, 71.38; H, 9.17; N, 4.40.
Methyl 5-Benzyl-2-butyl-4-hexanoyl-1H-pyrrole-3-carboxylate
(7b). Yield: 186 mg, starting from 285 mg of N-Boc-7-(1-amino-2-
phenylethyl)-trideca-5,8-diyn-7-ol 6b (73%) (Table 3, entry 2). Yellow
amorphous solid: mp = 94−96 °C; IR (KBr) ν = 3287 (m, br), 2956
(m), 2930 (m), 2872 (w), 1704 (s), 1673 (s), 1525 (m), 1495 (w),
1456 (s), 1367 (w), 1199 (m), 1160 (w), 1110 (m), 1076 (m), 755
(m), 728 (m), 696 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 8.83
(s, br, 1 H), 7.29−7.08 (m, 5 H), 3.94 (s, 2 H), 3.75 (s, 3 H), 2.75 (t,
J = 7.3, 2 H), 2.67 (t, J = 7.3, 2 H), 1.65−1.42 (m, 4 H), 1.37−1.18
(m, 6 H), 0.92−0.81 (m, 6 H); 13C NMR (75 MHz, CDCl3) δ = 203.0,
165.6, 139.4, 138.4, 131.8, 128.7, 128.6, 126.6, 123.7, 110.2, 51.0, 43.7,
32.2, 31.7, 31.6, 26.7, 24.6, 22.5, 22.4, 13.9, 13.8; GC−MS m/z = 369
(M+, 37), 338 (35), 337 (100), 308 (15), 298 (34), 295 (22),
294 (50), 281 (30), 279 (23), 278 (39), 266 (57), 252 (13), 239 (21),
196 (17), 168 (34), 167 (21), 115 (8), 91 (23), 73 (19). Anal. calcd
for C23H31NO3 (369.50): C, 74.76; H, 8.46; N, 3.79. Found: C, 74.85;
H, 8.44; N, 3.78.
Methyl 2-Butyl-4-hexanoyl-5-isobutyl-1H-pyrrole-3-carboxylate
(7c). Yield: 173 mg, starting from 261 mg of (S)-N-Boc-7-(1-amino-
3-methylbutyl)-trideca-5,8-diyn-7-ol 6c (75%) (Table 3, entry 3).
Yellow amorphous solid: mp = 40−42 °C; IR (KBr) ν = 3295 (m, br),
2957 (m), 2927 (m), 2871 (w), 1708 (s), 1675 (s), 1525 (m), 1449
(m), 1368 (m), 1193 (m), 1166 (m), 1091 (m), 1066 (w), 787 (w),
1
750 (w) cm−1; H NMR (300 MHz, CDCl3) δ = 9.14 (s, br, 1 H),
3.76 (s, 3 H), 2.81 (t, J = 7.7, 2 H), 2.69 (t, J = 7.7, 2 H), 2.40 (d, J =
7.7, 2 H), 1.92−1.74 (m, 1 H), 1.71−1.50 (m, 4 H), 1.40−1.23 (m,
6 H), 0.93−0.83 (m, 6 H), 0.82 (d, J = 6.5, 6 H); 13C NMR (75 MHz,
CDCl3) δ = 203.0, 165.7, 138.8, 133.1, 123.9, 110.2, 50.9, 43.9, 35.3,
31.8, 31.7, 29.3, 26.7, 24.6, 22.6, 22.44, 22.36, 13.9, 13.8; GC−MS m/z =
335 (M+, 21), 304 (15), 303 (36), 292 (17), 288 (22), 274 (10), 265
(16), 264 (100), 260 (50), 247 (18), 246 (11), 232 (17), 93 (27).
Anal. calcd for C20H33NO3 (335.48): C, 71.60; H, 9.91; N, 4.18.
Found: C, 71.65; H, 9.90; N, 4.17.
Methyl 2-Butyl-4-hexanoyl-5-isopropyl-1H-pyrrole-3-carboxylate
(7d). Yield: 150 mg, starting from 252 mg of N-Boc-7-(1-amino-2-
methylpropyl)-trideca-5,8-diyn-7-ol 6d (68%) (Table 3, entry 4).
Yellow amorphous solid: mp = 68−71 °C; IR (KBr) ν = 3217 (m, br),
2962 (m), 2934 (m), 2873 (w), 1711 (s), 1647 (s), 1529 (m), 1464
(m), 1384 (m), 1362 (m), 1206 (m), 1110 (m), 1077 (w), 792 (m)
cm−1; 1H NMR (300 MHz, CDCl3) δ = 9.05 (s, br, 1 H), 3.77 (s, 3 H),
3.27−3.12 (m, 1 H), 2.88−2.78 (m, 2 H), 2.74−2.65 (m, 2 H), 1.71−1.50
(m, 4 H), 1.40−1.24 (m, 6 H), 1.20 (d, J = 7.3, 6 H), 0.95−0.84 (m,
6 H); 13C NMR (75 MHz, CDCl3) δ = 203.9, 165.7, 139.2, 138.7, 121.9,
109.6, 51.0, 44.2, 31.9, 31.6, 26.8, 25.5, 24.8, 22.6, 22.51, 22.48, 14.0, 13.8;
GC−MS m/z = 321 (M+, 20), 290 (15), 289 (39), 278 (9), 260 (11),
251 (17), 250 (100), 246 (38), 233 (25), 232 (14), 218 (16), 204 (9),
191 (9), 176 (8), 164 (8), 148 (10), 132 (11), 120 (17), 107 (17), 106
(24), 79 (10). Anal. calcd for C19H31NO3 (321.45): C, 70.99; H, 9.72; N,
4.36. Found: C, 71.12; H, 9.70; N, 4.35.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
X-ray crystallographic data for product syn-3f and copies of H
and 13C NMR spectra for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: b.gabriele@unical.it.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Ministero dell’Istruzione, dell’Uni-
■
Methyl 5-Methyl-2-phenyl-4-phenylacetyl-1H-pyrrole-3-carboxy-
late (7e). Yield: 129 mg, starting from 260 mg of (S)-N-Boc-3-(1-
aminoethyl)-1,5-diphenylpenta-1,4-diyn-3-ol 6e (56%) (Table 3, entry 5).
Yellow oil: IR (film) ν = 3426 (m, br), 1701 (s), 1641 (s), 1525 (w),
1493 (w), 1437 (s), 1263 (m), 1194 (w), 1170 (w), 1127 (m), 1040 (w),
761 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 9.28 (s, br, 1 H), 7.43−
7.36 (m, 2 H), 7.32−7.10 (m, 8 H), 4.01 (s, 2 H), 3.68 (s, 3 H), 2.14 (s,
3 H); 13C NMR (75 MHz, CDCl3) δ = 197.6, 166.6, 135.1, 134.0, 133.6,
131.0, 129.6, 128.4, 128.3, 128.23, 128.16, 126.6, 122.6, 112.0, 51.7, 49.2,
12.7; GC−MS m/z = 333 (M+, 5), 301 (4), 243 (16), 242 (100), 212
(16), 128 (4), 115 (3), 104 (5), 91 (5). Anal. calcd for C21H19NO3
(333.38): C, 75.66; H, 5.74; N, 4.20. Found: C, 75.52; H, 5.75; N, 4.19.
Methyl 2-tert-Butyl-4-(3,3-dimethylbutanoyl)-5-methyl-1H-pyr-
role-3-carboxylate (7f). Yield: 134 mg, starting from 232 mg of (S)-
N-Boc-5-(1-aminoethyl)-2,2,8,8-tetramethylnona-3,6-diyn-5-ol 6f
(66%) (Table 3, entry 6). Yellow oil: IR (film) ν = 3334 (m, br),
2956 (m), 1711 (s), 1647 (m), 1522 (w), 1432 (m), 1366 (w), 1270
versita
̀
e della Ricerca (MIUR, Rome, Italy) is gratefully
acknowledged (Progetto di Ricerca d’Interesse Nazionale PRIN
2008A7P7YJ). Thanks are due to Dr. Giuseppe Chita (Istituto
di Cristallografia, CNR, Bari) for assistance in X-ray
diffractometric analysis.
REFERENCES
■
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4014
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