Regio- and Stereospecific Copper-Catalyzed Substitution Reaction of Propargylic Ammonium Salts with Aryl Grignard Reagents

Article abstract of DOI:10.1021/jacs.7b05273

We have developed a copper-catalyzed substitution reaction of propargylic ammonium salts with aryl Grignard reagents. The reaction is stereospecific and α-regioselective and proceeds with exceptional functional group tolerance. Conveniently, a stable, inexpensive, and commercially available copper salt is used and no added ligand is required.

Full text of DOI:10.1021/jacs.7b05273

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Communication
Regio- and Stereospecific Copper-Catalyzed Substitution Reaction
of Propargylic Ammonium Salts with Aryl Grignard Reagents
Manuel Guisán-Ceinos, Victor Martin-Heras, and Mariola Tortosa
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 Jun 2017
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Regio- and Stereospecific Copper-Catalyzed Substitution Reaction of
Propargylic Ammonium Salts with Aryl Grignard Reagents.
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Manuel Guisán-Ceinos†, Victor Martín-Heras† and Mariola Tortosa†§*
†Departamento de Química Orgánica, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid (Spain)
§Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid, 28049 Madrid, Spain
Supporting Information Placeholder
virtually unexplored.15 Therefore, finding new catalytic
ABSTRACT: We have developed a copper-catalyzed
systems based on stable and non-precious metals, and
substitution reaction of propargylic ammonium salts
expanding the structural scope of the ammonium salts,
are still unmet challenges. Progress in this area would
definitely expand the field of metal-catalyzed cleavage
of C-N bonds.
with aryl Grignard reagents. The reaction is stereospecif-
ic, α-regioselective and proceeds with exceptional func-
tional group tolerance. Conveniently, a stable, inexpen-
sive and commercially available copper salt is used and
no added ligand is required.
Scheme 1. Cross Coupling of Trimethylammonium
Salts
Transition-metal catalyzed reactions have emerged as
one of the most powerful tools for the formation of car-
bon-carbon bonds. Recently, significant efforts have
been made in this field to look for more stable and easily
available electrophiles. Different approaches for the
activation of C-H,1 C-C2 and C-O3 bonds have been
developed, providing chemists with a broad range of
new tools that is changing the design of synthetic strate-
gies. In this field, transition-metal catalyzed cleavage of
C-N bonds is less explored and still remains a chal-
lenge.4 This is not surprising considering the high bond
dissociation energy of the C-N bond.5 An attractive ap-
proach to bypass this problem is the transformation of
simple amines into ammonium salts, which are air and
thermally stable solids. Ammonium salts are readily
prepared from amine precursors, so they benefit from
the large variety of methods available to prepare nitro-
gen containing molecules.6
Following the pioneering work of Wenkert,7 several
groups have successfully used aryl and benzylic ammo-
nium salts in Kumada,8 Negishi,9 Suzuki,10 Buchwald-
Hartwig,11 and cross-electrophile12 couplings (Scheme 1,
eq. 1-2).13 However, despite their availability and stabil-
ity, the use of ammonium salts in metal-catalyzed reac-
tions is still relatively restricted, especially in stereose-
lective transformations. In this context, Watson has re-
ported the stereospecific Suzuki-Miyaura coupling of
chiral secondary benzylic ammonium salts,14 but other
secondary chiral salts remain unexplored (Scheme 1, eq.
3). Additionally, most of the reported examples require
the use of the air-sensitive and thermally unstable
Ni(cod)2. Surprisingly, the use of copper-catalysis is
Motivated by these challenges, we looked at second-
ary propargylic ammonium salts as potential electro-
philes for stereospecific metal-catalyzed transformations
(Scheme 1, eq. 4). They are readily available from the
amine precursors providing an alternative to the use of
highly reactive and often unstable propargylic bromides
and phosphates. Importantly, secondary propargylic
amines are stable precursors that can be prepared in high
enantiopurity from the corresponding alcohols or
through a variety of asymmetric catalytic methods.16 As
a drawback, secondary propargylic ammonium salts
present two possible reactive sites (the α and the γ posi-
tions) that could lead to mixtures of formal SN2 or SN2’
products. Therefore, a successful catalytic system should
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be able to control both the regio- and the stereoselectivi- 40:60 mixture of propargylic derivative 2a and allene 3a
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ty. In this communication, we describe our efforts to-
ward this goal using a copper salt and aryl Grignard
reagents. The reaction is stereospecific and completely
α-regioselective, which is striking for copper-catalyzed
transformations of propargylic electrophiles. The reac-
tion proceeds well with a commercially available and
inexpensive copper salt and without the need of an add-
ed ligand.17
in low yield (Table 1, entry 1). Changing to
[Ni(dppe)]Cl2 eliminated formation of allene 3a, and
compound 2a was isolated in low yield along with the
corresponding propargylic bromide (Table 1, entry 2).
Based on our previous experience in copper-catalyzed
transformations,19 we decided to test the use of copper
catalysis. Using CuCl (10 mol%) in THF at −40 ºC we
observed the immediate formation of the α-product (R)-
2a in high yield and moderate enantiomeric ratio (Table
1, entry 3). The reaction was extremely fast (5 min) at
−40 ºC and only 1.1 equivalents of the Grignard reagent
were needed. Therefore, it was reasonable to predict a
broad functional group compatibility, despite the high
reactivity of the nucleophiles. Importantly, allene 3a was
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Table 1. Optimization of the Reaction Conditions
OMe
MeO
NMe3
X
catalyst
solvent, T
H
Me
1
•
not detected in the H NMR of the crude product, an
unusual result in copper-catalyzed reactions of propar-
gylic electrophiles.20,21
Ph
+
Me
Ph
Me
OMe
BrMg
Ph
(R)-1a
er = 99:1
(R)-2a
3a
We were pleased to find that switching to
Cu(CH3CN)4PF6 (10 mol%) significantly improved both
the yield and the enantioselectivity, affording (R)-2a
with complete inversion of the configuration (Table 1,
entry 4).22 When the reaction was run at higher tempera-
tures (0 and −20 ºC), we observed a slight erosion of the
enantiomeric ratio (Table 1, entries 5 and 6). The cata-
lyst loading was reduced to 5 mol% without affecting
the yield or the stereoselectivity (Table 1, entry 7). The
reaction also worked well in CH2Cl2, which improved
the solubility of the ammonium salt (Table 1, entry 8).
Interestingly, the counterion on the ammonium salt was
not an innocent witness (Table 1, entries 8-12). Our
results show that the triflate anion plays a key role in
tuning the yield and enantioselectivity. In the absence of
a copper salt at −40 ºC, no product formation was ob-
served (Table 1, entry 13). At room temperature, howev-
er, 2a was obtained in low yield and poor enantiomeric
ratio (Table 1, entry 14). These two experiments show
the crucial role of the copper-salt in the reaction.23
Entry
Catalyst
LG
T
(ºC)
era
yield
2a
(%)b
12d
22f
80
1c
Pd(PPh3)2Cl2
[Ni(dppe)]Cl2
CuCl
NMe3OTf
NMe3OTf
NMe3OTf
NMe3OTf
NMe3OTf
NMe3OTf
NMe3OTf
NMe3OTf
NMe3OMs
rt
n.d.
n.d.
2e
rt
3 g
4 g
5 g
6 g
7h
8h,i
9
85:15
99:1
95:5
94:6
99:1
99:1
94:6
−40
−40
−20
0
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
98
96
94
95
−40
−40
−40
98
58
10
11
12
13
14
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6

NMe3BF4
NMe3I
94:6
94:6
98:2
68
58
56
−40
−40
−40
−40
rt
NMe3OTs
NMe3OTf


NMe3OTf
54:46
22

Encouraged by these results, we prepared a series of
racemic secondary propargylic ammonium salts to de-
termine first the structural scope of the transformation
(Scheme 2). Using the optimized conditions with phenyl
magnesium bromide, we obtained compound 2b in ex-
cellent yield. Our conditions allowed a wide variety of
functional groups on the aromatic ring (R1) of the am-
monium salt, at the ortho, meta and para positions
(compounds 2c-2k). High yields were observed for sub-
strates with electron withdrawing groups (compounds
2c-2i). Remarkably, even sensitive groups like esters
(compounds 2d and 2e) and ketones (compound 2f)
were tolerated. In particular, the chemoselectivity ob-
served with compound 2f (while not complete) demon-
strates the functional group compatibility.24 Importantly,
aryl chloride and bromide derivatives react exclusively
through the C-N bond under copper-catalysis (com-
pounds 2h and 2i). We also carried out the reaction at
b
c
aDetermined by chiral SFC. Isolated yields. Conditions with
Pd: 1a (0.1 mmol, 1.0 equiv.), ArMgX (1.1 equiv.), Pd(PPh3)2Cl2
(10 mol%), THF (0.1 M), 4 h. d40:60 mixture of 2a and 3a. eCon-
ditions with Ni: 1a (0.1 mmol, 1.0 equiv), ArMgX (1.1 equiv.),
[Ni(dppe)]Cl2 (10 mol%), THF (0.1 M), 4 h. f2a was isolated with
g
the corresponding propargylic bromide as a 82:18 mixture. Con-
ditions with Cu: 1a (0.1 mmol, 1.0 equiv.), ArMgX (1.1 equiv.),
CuX (10 mol%), THF (0.1 M), −40 ºC, 5 min, unless otherwise
noted. 5 mol% of Cu(CH3CN)4PF6 was used. CH2Cl2 was used
instead of THF.
h
i
Propargylic ammonium salt (R)-1a was easily pre-
pared from the corresponding (S) propargylic alcohol
through a one-pot mesylation/amination with dimethyl-
amine, followed by treatment with methyl triflate.18 To
explore the reactivity of these novel electrophiles, we
first chose highly reactive nucleophiles such as aryl
Grignard reagents. When we tried palladium catalyzed
Kumada conditions, previously reported for aryltrime-
thylammonium salts, we observed the formation of a
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gram scale with compound 2h without affecting the secondary substrates are more reactive than primary
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yield.
ammonium salts in the copper-catalyzed reaction. The
yield for compound 2q was improved to 69% when the
reaction was carried out at room temperature. The cou-
pling also worked with a variety of aryl Grignard rea-
gents with electron-withdrawing (compounds 2s, 2t) and
electron-donating groups (compound 2u). In all cases,
we observed exclusive substitution at the α-position.
Scheme 2. Scope of the Substitution Reaction of Pro-
pargylic Ammonium Salts
9
Scheme 3. Stereospecific Substitution Reactionsd
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Ph
Me
Ph
Me
Ph
Me
Ph
Me
CO2Me
Ph
MeO2C
Ph
F3C
2b, 91%
2c, 84%
Ph
Me
2e, 60%
2d, 83%
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Me
Br
O
F
O
Cl
MeO2C
Me
(R)-2d, 81%
er = 99:1
es = >99%a
(R)-2f, 52%
er = 98:2
es = 98%a
(R)-2b, 95%
er = 99:1
es = >99%a
2g, 90%
Ph
Me
2h, 96% (93%)a
2f, 52%
2i, 93%
Me
Ph
Me
Ph
Me
Ph
Me
Cl
OMe
TMS
Ph
S
MeO
Me
2k, 89%
OMe
Ph
2l, 81%
2j, 94%
Ph
2m, 80%
Me
Me
Br
Ph
Ph
Ph
C6H13
Ph
Me
Ph
Ph
OMe
(R)-2v, 79%
er = 99:1
es = >99%a
(R)-2k, 97%
er = 98:2
es = 98%a
MeO2C
(R)-2u, 84%
er = 99:1
es = >99%a
Ph
Ph
TMS
2n, 88%b
Cl
2o, 73%b
2p, 81%b
2q, 50% (69%)c
OMe
2r, 69%
OMe
OMe
F
Ph
Bu
TMS
Bu
Bu
Me
Me
Me
TMS
(R)-2y, 87%
er = 92:8
es = 98%b
TMS
(R)-2x, 82%
er = 91:9
es = 95%b
(R)-2w, 92%
er = 93:7
es = >99%b
MeO2C
OMe
OMe
aStarting material er = 99:1. Starting material er = 93:7. Enanti-
ospecificity (es)= eeproduct/eestarting materialx100%.
b
c
2t, 93%
2s, 95%
2u, 82%
aReaction performed with 1 gram of ammonium salt. General
conditions were used except for Cu(CH3CN)4PF6 (10 mol%) and
CH2Cl2 (0.03 M). cThe reaction was carried out at 23 ºC.
b
Next, we checked if the stereospecificity observed for
(R)-1a (Table 1) was general for different ammonium
salts and Grignard reagents (Scheme 3). Ammonium
salts with aryl and silyl substitution on the alkyne and
different alkyl chains at the propargylic position afford-
ed the desired compounds in high yield and with excel-
lent chirality transfer. Interestingly, the method allows
for the preparation of enantiomerically enriched bifunc-
tional compounds such as 2v, with two orthogonal hal-
ide substituents which would be difficult to prepare
using other transition metals.
Similarly, compounds with electron donating groups
(compound 2j) and heterocycles (compound 2l) were
prepared in excellent yield. Further structural modifica-
tions in the ammonium salt such as silyl and alkyl sub-
stitution in the alkyne (compounds 2m and 2n) and dif-
ferent alkyl chains at the propargylic position (com-
pounds 2o and 2p) are also allowed. For compounds 2n,
2o and 2p, we had to increase the amount of solvent and
catalyst loading (10 mol%) to achieve good conversion.
This lower reactivity could be due to stereoelectronic
effects of the substituents on the alkyne (2n) and propar-
gylic carbon (2o, 2p). Surprisingly, primary ammonium
salts gave only moderate yields (compounds 2q and 2r)
at –40 ºC. A competition experiment between ammoni-
um salts 1a (1 equiv.) and 1q (1 equiv.) with 1 equiv. of
Grignard reagent, under standard reaction conditions,
afforded 61% of 2b and only 5% yield of 2q (see Sup-
porting Information). This experiment suggests that
Although further mechanistic studies need to be im-
plemented, our results support an SN2 mechanism in-
volving addition of a catalytically generated aryl cuprate
to the ammonium salt. The lower reactivity observed for
primary ammonium salts compared to secondary deriva-
tives (compounds 2q and 2r), could suggest a substantial
amount of carbon-nitrogen bond rupture in the transition
state.25
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(11) Zhang, X.-Q.; Wang, Z.-X. Org. Biomol. Chem. 2014, 12,
1448.
(12) Moragas, T.; Gaydou, M.; Martin, R. Angew. Chem. Int. Ed.
2016, 128, 5137.
(13) For a Ni catalyzed reduction of aromatic and benzylic ammo-
nium salts, see: Yi, Y-Q-Q.; Yang, W-C.; Zhai, D-D.; Zhang, X-Y.;
Li, S-Q.; Guan, B-T. Chem. Comm. 2016, 52, 10894.
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During the preparation of this manuscript, the same group reported
the first Ni catalyzed cross-coupling of alkyl pyridinium salts: (c)
Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P. J. Am. Chem.
Soc. 2017, 139, 5313.
(15) (a) Dressaire, G.; Langlois, Y. Tetrahedron Lett. 1980, 21, 67.
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2947.
(16) Selected enantioselective methods to prepare secondary pro-
pargylic alcohols: (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738. (b) Anand, N. K.;
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Knochel, P. Angew. Chem. Int. Ed. 2003, 42, 5763. (e) Akullian, L.
C.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42,
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13624. (h) Paioti, P. H. S.; Abboud, K. A.; Aponick, A. J. Am. Chem.
Soc. 2016, 138, 2150.
(17) For an enantioselective nickel-catalyzed Negishi coupling of
propargylic bromides to obtain similar compounds, see: Smith, S. W.;
Fu, G. C. J. Am. Chem. Soc. 2008, 130, 12645.
(18) The absolute configuration for ammonium salt (R)-1i (Scheme
2) was established by single crystal X-ray crystallography. CCDC
1546939 contains the supplementary crystallographic data for (R)-1i.
In summary, we have developed a stereospecific
1
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3
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5
6
7
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method for the catalytic Kumada type coupling of sec-
ondary propargylic ammonium salts with aryl Grignard
reagents. We show for the first time that propargylic
ammonium salts are suitable partners in metal-catalyzed
reactions. Conveniently, a stable, inexpensive and com-
mercially available copper salt is used and no added
ligand is required. Surprisingly, only the α-regioisomer
is formed, which is striking for copper-catalyzed trans-
formations. Additional studies on stereospecific copper-
catalyzed coupling reactions of ammonium salts are
underway.
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ASSOCIATED CONTENT
Experimental procedures, compound characterization data,
analytic details for all enantiomerically enriched products
and crystal structural data. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
mariola.tortosa@uam.es
Notes
No competing financial interests have been declared.
ACKNOWLEDGMENT
We thank the European Research Council (ERC-337776)
and MINECO (CTQ2016-78779-R) for financial support.
M. T. thanks MICINN for a RyC contract. V. M-H. thanks
UAM for a predoctoral fellowship. We acknowledge Dr.
Josefina Perles for X-ray structure analysis.
These
www.ccdc.cam.ac.uk/conts/retrieving.html.
data
can
be
obtained
free
of
charge
at
(19) (a) Guisan-Ceinos, M.; Parra, A.; Martin-Heras V.; Tortosa M.
Angew. Chem. Int. Ed. 2016, 55, 6969. (b) Jarava-Barrera, C.; Parra,
A.; López, A.; Cruz-Acosta, F.; Collado-Sanz, D.; Cárdenas, D. J.;
Tortosa M. ACS Cat. 2016, 6, 442. (c) Lopez, A.; Parra, A.; Jarava-
Barrera, C.; Tortosa, M. Chem. Comm 2015, 51, 17684. (d) Parra, A.;
Amenós, L.; Guisan-Ceinos M.; López, A.; Garcia-Ruano, J. L.;
Tortosa, M. J. Am. Chem. Soc. 2014, 136, 15833. (e) Alfaro, R;
Parra, A.; Alemán, J.; Garcia-Ruano, J. L.; Tortosa, M. J. Am. Chem.
Soc. 2012, 134, 15165-15168. (f) Tortosa, M. Angew. Chem. Int. Ed.
2011, 50, 3950.
(20) Recently, Trost reported unsual SN2 stereocontrol using sec-
ondary propargylic bromides and stoichiometric diorganocuprates
generated from lithiated heterocycles and CuCN (1 equiv). However,
with arene nucleophiles they observed a 1:1 ratio of alkyne:allene
products: Trost, B. M.; Debien, L. Chem. Sci. 2016, 7, 4985.
(21) (a) Yang, M.; Yokokawa, N.; Ohmiya, H.; Sawamura, M.
Org. Lett. 2012, 14, 816. (b) Uehling, M. R.; Marionni, S. T.; Lalic,
G. Org. Lett. 2012, 14, 362.
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(9) Xie, L.-G.; Wang, Z.-X. Angew. Chem. Int. Ed. 2011, 50, 4901.
(10) (a) Blakey, S. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2003, 125, 6046. (b) de la Herran, G.; Csákÿ, A. G. Org. Lett. 2007,
9, 961. (c) Zhang, H.; Hagihara, S.; Itami, K. Chem. Eur. J. 2015, 21,
16796.
(22) See Supporting Information for details on the determination of
the absolute configuration of the products.
(23) The corresponding propargylic mesylate afforded 2a with
lower yield and reduced enantioselectivity. The propargylic phosphate
gave an inseparable 95:5 mixture of 2a and allene 3a. Both, mesylate
and phosphate derivatives decomposed quickly and could not be
stored. These results highlight the benefit of using an ammonium salt
as leaving group. See Supporting Information for details.
(24) 20 % of starting material along with products derived from the
addition of the Grignard reagent to the carbonyl were identified in the
1H NMR of the crude product.
(25) Westaway, K. C.; Poirier, R. A.; Can J. Chem. 1975, 53,
3216.
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