Mild and efficient desymmetrization of diynes via hydroamination: Application to the synthesis of (±)-monomorine I

Article abstract of DOI:10.1021/jo902674j

(Chemical Equation Presented) An efficient silver-catalyzed desymmetrization of amino diynes via hydroamination is reported. A variety of functionalized 1-pyrroline derivatives were synthesized in 73% to 88% isolated yields (>98% by ¹H NMR in some cases). The usefulness of this mild hydroamination method was further shown by the desymmetrization of unprotected tert-hydroxy diynes. Structures of two transition states have been studied computationally. An application of this method was demonstrated by a short and efficient synthesis of (±)-monomorine I. 2010 American Chemical Society.

Full text of DOI:10.1021/jo902674j

pubs.acs.org/joc
hydroamination/cyclization of aminoalkynes,3-5 amino-
Mild and Efficient Desymmetrization of Diynes via
Hydroamination: Application to the Synthesis of (()-
Monomorine I
alkenes,6-9 aminoallenes,10,11 and aminodienes12,13 has been
documented in numerous studies. The search for appropriate
metal catalysts for these reactions has been the subject of
extensive research, particularly for hydroamination of al-
kenes and alkynes.1 The hydroamination of alkynes has been
reported to proceed in the presence of various metals such as
lithium,14 group 4 metals,15 nickel,16 palladium,17-19 plati-
num,20 calcium,21 copper,22 gold,23 and zinc.24 Although
good catalytic hydroamination conditions have been devel-
oped, many of the metals used are expensive, and the
susceptibility of some of their complexes to moisture and
oxygen constitutes a serious drawback in many cases.
Vijaya Bhaskara Reddy Iska, Vincenzo Verdolino,
Olaf Wiest,* and Paul Helquist*
Department of Chemistry and Biochemistry, University of
Notre Dame, 251 Nieuwland Science Hall, Notre Dame,
Indiana 46556
phelquis@nd.edu; owiest@nd.edu
Received December 18, 2009
SCHEME 1. Hydroamination of Aminoalkyne3
As part of an ongoing program directed toward the
development of new methodologies for transition metal-
catalyzed reactions in our laboratory,25-28 we previously
reported an efficient intramolecular hydroamination of ami-
noalkynes (Scheme 1) using catalytic amounts of a silver-
(1,10-phenanthroline)OTf complex, Ag(phen)OTf, which is
highly stable toward moisture and air, employs a metal
having moderate cost, and is readily recyclable.3
Our earlier results suggested the utility of this reaction for
desymmetrization of diynes via intramolecular hydroamina-
tion. Desymmetrization of many classes of compounds in-
cluding alkynes29-32 is an efficient strategy to generate useful
An efficient silver-catalyzed desymmetrization of amino
diynes via hydroamination is reported. A variety of
functionalized 1-pyrroline derivatives were synthesized
1
in 73% to 88% isolated yields (>98% by H NMR in
some cases). The usefulness of this mild hydroamination
method was further shown by the desymmetrization of
unprotected tert-hydroxy diynes. Structures of two tran-
sition states have been studied computationally. An
application of this method was demonstrated by a short
and efficient synthesis of (()-monomorine I.
(11) Hoover, J. M.; Petersen, J. R.; Pikul, J. H.; Johnson, A. R. Organo-
metallics 2004, 23, 4614.
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Nitrogen-containing heterocycles are found among many
biologically important compounds. Their synthesis via the
intramolecular hydroamination of C-C multiple bonds, an
atom economical process,1,2 is a subject of great interest in
synthetic organic chemistry. Metal-catalyzed intramolecular
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Soc. 2009, 131, 410.
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O.; Helquist, P. J. Org. Chem. 2008, 73, 3911.
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DOI: 10.1021/jo902674j
r
Published on Web 01/20/2010
J. Org. Chem. 2010, 75, 1325–1328 1325
2010 American Chemical Society

Iska et al.
JOCNote
SCHEME 2. Hydroamination of Diynes 1a-c
TABLE 2. Hydroamination of Diynes 3a-c
mol temp time yield
(%)a
entry substrate
R
catalyst
%
(°C)
(h)
1
2
3
4
5
6
3a
3a
3a
3b
3b
3c
nBu Ag(Phen)OTf
nBu Ag(Phen)OTf
nBu Ag(Phen)OTf
5
2
2
5
2
5
50
50
rt
rt
50
50
2
3
10
10
5
85
87
69
-
73
80
Ph
Ph
Ag(Phen)OTf
Ag(Phen)OTf
TABLE 1. Hydroamination of Diynes 1a-c
tBu Ag(Phen)OTf
8
aisolated yields.
temp time
mol % (°C) (h)
yield
(%)
entry substrate
R
catalyst
AgOTf
SCHEME 4. Hydroamination of Diyne 5
1
2
1a
1a
H
H
10 25
Ag(Phen)OTf 10 25 <5 min
1
<5a
>98a
(85)b
>90a
(82)b
>90a
88b
3
1b
Ph Ag(Phen)OTf 10
25
4
4
5
6
7
1c
1c
1a
1b
Me Ag(Phen)OTf 10
Me Ag(Phen)OTf 10
25
50
6
2
H Ag(Phen)OTf
Ph Ag(Phen)OTf
2
2
25 <5 min
50
>98a
>90a
(83)b
>98a
1
of the reaction in the presence of a potentially interfering
functional group. For this purpose, hydroxyaminodiynes
3a-c were prepared from β-alanine by standard transforma-
tions.17 This series of compounds also provide an altered
substrate skeleton for generating 1-pyrrolines 4 (Scheme 3)
having a modified substitution pattern compared to 2.
After applying the previously utilized hydroamination
conditions optimized for 1a-c, we found that either an
extension of the reaction time or an increase in reaction
temperature is required to cyclize 3a-c. The diyne 3a was
cyclized to 4a with 5 mol % of Ag(phen)OTf at 50 °C for 2 h
in 85% yield (entry 1, Table 2). A lower amount of catalyst of
Ag(phen)OTf (2 mol %) also gave 4a at 50 °C in essentially
the same yield (entry 2). Lowering the reaction temperature
to 25 °C reduced the reaction rate, but gave 4a in moderate
yield (entry 3). The phenyl-substituted diyne 3b did not
undergo hydroamination at room temperature but at 50 °C
readily underwent cyclization with 5 mol % of Ag(phen)OTf
for 5 h to give 4b in 73% yield. Similarly, the diyne 3c also
gave4cat 50 °C in 80% yield with 5 mol % of catalyst (entry 5).
To examine another substrate skeleton, amino diyne 5 was
synthesized (Scheme 4).17 This substrate was also chosen to
examine the effect of silylated alkyne groups. Furthermore, 5
could be employed as the starting point for a natural product
synthesis (vide infra). The diyne 5 underwent cyclization with
5 mol % of Ag(phen)OTf for 8 h at 50 °C to give 6 in 92%
yield. Interestingly, desilylation was observed only from the
alkyne group that underwent the hydroamination.
8
1a
H
Ag(Phen)OTf
0.5
25
1
aYields measured by 1H NMR of the crude material. bIsolated yields.
SCHEME 3. Hydroamination of Diynes 3a-c
building blocks in organic synthesis. Here we demonstrate
the utility of this concept for the synthesis of a range of
functionalized 1-pyrroline derivatives. In addition to the
development of a diyne desymmetrization, we have also
perfomed DFT studies of two possible transition states for
this reaction.
As an initial class of substrates, we chose to study the
aminodiynes 1a-c (Scheme 2), which are easily accessible
from commercially available starting materials by standard
transformations.33 The results of the hydroaminations of
1a-c are summarized in Table 1.
A control reaction was performed with 1a, using 10 mol %
AgOTf without any ligand, but almost no reaction was
observed (entry 1). This result suggests the requirement for
a suitable ligand for the desired reaction in this system. The
catalyst generated from AgOTf and 1,10-phenanthroline
produced the cyclic imine 2a as the sole detectable product
(>98% yield by 1H NMR) from diyne 1a at room tempera-
ture (entry 2). The same catalyst converted 1b to 2b (>90%
yield by 1H NMR) at room temperature (entry 3). The diyne
1c underwent cyclization slowly at room temperature to give
2c with 10 mol % of Ag(phen)OTf (entry 4). However, an
increase in temperature to 50 °C significantly shortened the
reaction time (entry 5). Interestingly, lowering the amount of
catalyst from 10 mol % to 2 mol % also produced the
products 2a and 2b in over 90% yields (entries 6 and 7),
whereas 1a underwent cyclization to give 2a with even
0.5 mol % catalyst for 1 h (entry 8).
To gain a better understanding of the silver-catalyzed
hydroamination and to explore the effects of substituted
phenanthroline ligands, we calculated the relevant transition
structures at the B3LYP34,35/LanL2DZ36,37 level of theory in
analogy to our previous work.28 We considered a simplified
model, the hydroamination of acetylene with ethylamine
catalyzed by
a (2-methylphenathroline)silver complex
(Figure 1). In this model, the two possible region isomeric
transition structures anti-TS1 and syn-TS2 are possible. The
energy difference between the two can serve as a measure of
the regio- or stereochemical differentiation that a substitu-
ent, including chiral groups, on the ligand may have on the
reaction. The two transition states were fully optimized
After observing promising hydroamination results with
diynes 1a-c, we were interested in testing the compatibility
(34) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
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(33) See the Supporting Information
1326 J. Org. Chem. Vol. 75, No. 4, 2010

Iska et al.
JOCNote
SCHEME 5. Synthesis of (()-Monomorine
FIGURE 1. Representation of the Ag(I) 2-methyl, o-phenanthro-
line diastereomers for the acetylene amination transition state
model.
explored in order to introduce stereoselectivity in future
studies of the hydroamination reaction. These conclusions
will also apply to potential chiral substitutents larger than
methyl26 as shown by two characteristics of the model ligand
considered here: (1) the ligand is planar, and the silver
preferentially coordinates in a square-planar fashion, leaving
the triple bond open to attack from any direction; (2)
substituents at C(2) of the phenanthroline ligand are not in
the path of the nucleophile and thus are not sufficiently close
to the prochiral alkyne substrate to impact the potential
enantioselectivity of the reaction. Preliminary results of simi-
lar calculations extended to chiral phenanthroline derivatives
and BOX-type ligands confirm that even with bulky substit-
uents, an enantioselective desymmetrization is not readily
achievable because of the silver square-planar coordination.
On the basis of the foregoing experimental results, we
chose to demonstrate the utility of the desymmetrization
reaction by performing a synthesis of the alkaloid (()-
monomorine I. (þ)-Monomorine is an indolizidine alkaloid
isolated from the cosmopolitan ant Monomorium pharaoins
L.39 Along with other indolizidine alkaloids,40 both natural
(þ)-monomorine and nonnatural (-)-monomorine have
FIGURE 2. Optimized isomeric transition structures for the hydro-
amination model. Most important atomic distances are reported for
TS1 and TS2 transition states.
without any constraints by using the Berny algorithm im-
plemented in Gaussian03.38
The final structures with highlighted parameters are
shown in Figure 2. Structurally, TS1 and TS2 are essentially
identical and the calculated energy difference is much smaller
than what can be considered significant at this level of
theory. This weak differentiation indicates that 2-substituted
phenanthrolines are unlikely to induce significant regio- or
stereoselectivity. The coordinated carbon shows a Ag-C
˚
bond length of 2.24 A, which is significantly shorter than that
˚
for the carbon undergoing nucleophilic attack (2.69 A). The
˚
partial triple bond (1.26 A) is longer in both transition states
˚
than in uncoordinated acetylene (1.20 A). This indicates dona-
tion into the antibonding π* orbital, thus weaking the back-
bonding from silver upon nucleophilic attack of the amine.
Rehybridization of the alkyne has progressed significantly, but
been the target of many syntheses.41-47 Particularly relevant
47
˚
€
to the present study were the syntheses reported by Backvall
the N-C distance of 2.50 A in the transition structures is quite
and Toyooka,43 who used ketone 11 as a key intermediate.
Our route (Scheme 5) begins with the aforementioned cycli-
zation of diyne 5, which was synthesized from 4-bromo-1-
butyne.48
long, indicating a relatively early transition state. These differ-
ences are again due to the changes from dicoordination to
monocoordination of the alkyne to the silver.
The structural and energetic similarities between the two
transition states suggest that a different approach needs to be
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J. Org. Chem. Vol. 75, No. 4, 2010 1327

Iska et al.
JOCNote
The resulting cyclic imine 6 was subjected to chain exten-
sion by lithiation49 of the methyl group and subsequent
reaction with n-propylbromide to give imine 7 in 83% yield.
This imine was subjected to a one-pot conversion involving
DIBAL reduction,50 Cbz protection, and TBS removal51
without purification of intermediates to give pyrrolidine 8
in 64% overall yield. The alkyne 8 was converted to aldehyde
9 in a one-pot, two-step transformation by employing Kno-
chel’s hydroboration procedure52,53 and alkenylborane oxi-
dation with Me3NO54 in 81% overall yield. The aldehyde 9
was then treated with MeMgBr to obtain the alcohol 10 in
87% yield, followed by oxidation with the Dess-Martin
periodinane to give the previously employed ketone43,47,55 11
in 94% yield. A combination of hydrogenolysis and reduc-
tive amination of 11 with Pd/C and H2 in ethanol gave (()-
monomorine 12 in 82% yield. The overall yield is 26% for 7
steps.
having two entirely different, orthogonal functional groups,
each of which is independently capable of undergoing further
diverse transformations. As such this reaction is amenable to
the synthesis of a variety of useful intermediates and natural
products as demonstrated by the synthesis of (()-monomor-
ine I. A remaining need is the development of an enantiose-
lective version of this reaction.
Experimental Section
General Procedure (GP1) for the Hydroamination. To a solu-
tion of aminodiyne (1 mmol) in CH3CN (4 mL) was added
Ag(phen)OTf (0.1 mmol). The mixture was heated to 50 °C by
use of an oil bath for 4 h in the absence of light. The reaction
mixture was then cooled to 25 °C, passed through a column of
silica gel, and eluted with EtOAc/hexanes (1/9). Solvent eva-
poration gave the 1-pyrroline as a clear oil.
In conclusion, we have developed an efficient procedure
for desymmetrization of diynes by means of the silver-
catalyzed intramolecular hydroamination. This method
shows reliability in producing functionalized 1-pyrroline
derivatives in good to excellent yields. A key strategic feature
of this reaction is that it converts a diyne into a product
Acknowledgment. We gratefully acknowledge financial
support of this work by the Petroleum Research Fund
(Grant PRF no. 47810-AC1) and the National Science
Foundation (NSF CHE0833220) as well as generous alloca-
tion of computational resources on the TeraGrid (Grant TG-
CHE090124).
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Note Added after ASAP Publication. Typographical correc-
tions have been made to the version that published ASAP on
January 20, 2010. The corrected version was reposted on
January 29, 2010.
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Supporting Information Available: Starting material pre-
paration, characterization data for all new compounds, 1H and
13C spectra, and Cartesian coordinates and energies for the
calculated transition structures. This material is available free of
charge via the Internet at http://pubs.acs.org.
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1328 J. Org. Chem. Vol. 75, No. 4, 2010