Silver-Catalyzed Enantioselective Propargylation Reactions of N-Sulfonylketimines

Article abstract of DOI:10.1021/acs.orglett.5b02692

The enantioselective silver-catalyzed propargylation of N-sulfonylketimines is described. This reaction proceeds in high yield and excellent enantiomeric ratio and is compatible with a wide variety of diaryl- and alkylketimines. Synthetic transformations

Full text of DOI:10.1021/acs.orglett.5b02692

Letter
pubs.acs.org/OrgLett
Silver-Catalyzed Enantioselective Propargylation Reactions of
N‑Sulfonylketimines
Charlotte A. Osborne, Thomas B. D. Endean, and Elizabeth R. Jarvo*
Department of Chemistry, University of California, Irvine, California 92697, United States
S
* Supporting Information
ABSTRACT: The enantioselective silver-catalyzed propargylation of N-
sulfonylketimines is described. This reaction proceeds in high yield and
excellent enantiomeric ratio and is compatible with a wide variety of diaryl-
and alkylketimines. Synthetic transformations of homopropargylic
products via enyne ring-closing metathesis, Sonogashira cross-coupling,
and reduction reactions proceed with high stereochemical fidelity. Both
allenyl and propargyl borolane reagents can be used to obtain
homopropargylic products, a distribution most consistent with a
mechanism involving transmetalation of the silver catalyst with the
borolane reagent.
Table 1. Optimization of Silver-Catalyzed Propargylation
early half of the top 200 pharmaceuticals in 2012 contain
Reaction
N
functional groups that can be prepared from α-chiral
amines.1 To access this moiety, numerous enantioselective
methods for the synthesis of chiral amines have been developed,
many of which involve addition of organometallic nucleophiles to
aldimines.2 Additions to ketimines pose specific challenges. For
example, mixtures of E and Z isomers can lead to low levels of
enantioinduction.3 These obstacles have inspired creative
approaches4 including use of cyclic N-sulfonylketimines (e.g.,
1),whichdonotundergoE/Zisomerizationandaresynthesizedin
one step from saccharin.5,6 Hayashi and co-workers have
pioneered the rhodium-catalyzed enantioselective arylation
reactions of N-sulfonylketimines; other elegant examples of
arylation, allylation, and alkenylation reactions have also been
reported.5c,7 An enantioselective propargylation reaction would
afford a chiral sultam with a pendant terminal alkyne, a valuable
functional group handle that can be easily derivatized for further
synthetic elaboration.8 In this paper, we report the first
enantioselective propargylation reaction of ketimines (eq 1).
a
yield
b
entry
deviation from standard conditions
(%)
er
1
2
none
51
19
99:1
96:4
c
catalyst preformed in MeOH and reaction run in
THF
3
4
5
6
7
8
Walphos-8 instead of Walphos-1
Josiphos-6 instead of Walphos-1
(S)-BINAP instead of Walphos-1
reaction performed at 4 °C
35
70
55
54
57
76
76:24
74:26
40:60
99:1
reaction performed at rt
98:2
reaction performed at rt with 4 equiv 2
99:1
Building on early advances in enantioselective propargylation
reactions of aldehydes, in the past five years there has been rapid
development of enantioselective propargylation reactions of
ketones and aldimines.9−11 Our laboratory has reported the
silver-catalyzed enantioselective propargylation reactions of
aldimines and diaryl ketones.10b,12,13 Using AgF and chiral
phosphine ligands from the Walphos family provided a variety of
homopropargylic amines and alcohols in good yield and high
enantiomericexcess(ee).WereasonedthataAg/Walphoscatalyst
would be able to differentiate between the Re and Si faces of
diarylketimines, based on their structural similarity to diaryl
a
1
Determined using H NMR by comparison to PhTMS as internal
b
c
standard. Determined using chiral SFC. Preparation of Ag/Walphos
catalyst performed according to ref 10b.
ketones. Indeed, we found that employing AgPF6 with Walphos-1
resulted in formation of homopropargylic amine 3a in 99:1
enantiomeric ratio (er) and modest yield (Table 1, entry 1). In
Received: September 17, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Scope of Diaryl Sultams
Scheme 2. Scope of Alkyl Sultams
a
Absolute configuration assigned by X-ray crystallographic analysis.17
Scheme 3. Synthetic Transformations of Homopropargylic
Sultams
a
b
6 equiv allenylboronic acid pinacol ester 2 were employed. Absolute
configuration assigned by X-ray crystallographic analysis.16
comparison, preforming the catalyst in methanol and running the
reaction in THF gave high er but only 19% product (entry 2).14
Other chiral ferrocene-based ligands such as Walphos-8 and
Josiphos-6 provided lower er (entries 3 and 4), as did (S)-BINAP
(entry 5).
We further modified the reaction conditions to improve the
yield.Wefoundthatatambienttemperature3awasstillformedina
modest yield; fortunately, the er remained high (Table 1, entry 7).
We hypothesized that protodeborylation of allenylboronic acid
pinacol ester 2 to allene (C3H4) was competitive with the desired
addition reaction and thus resulted in modest yields.15 Use of an
additional 2 equiv of allenylboronic acid pinacol ester 2 via slow
addition increased the yield, providing 3a in 76% yield and 99:1 er
(entry 8).
Having determined optimized conditions for this reaction, we
proceeded to evaluate the substrate scope. A wide range of
arylketimines underwent enantioselective propargylation in high
yield and >95:5 er (Scheme 1). Ketimines containing electron-
withdrawing groups formed products in excellent er (3b−d). We
weregratifiedtofindthatsubstrateswithelectron-donatinggroups
participated inthis reaction, as the starting ketimines are generally
less reactive. 4-Methoxyphenyl-substituted sultam 3e was
generated in good yield and excellent er upon using 6 equiv of
allenylboronic acid pinacol ester 2. In addition, several hetero-
cycles were tolerated in the reaction. Ketimines containing furan,
thiophene, and benzothiophene functional groups reacted
smoothly to provide the corresponding homopropargylic
sulfonamides (3f−h) in high er. The absolute configurations of
3a, 3f, and 3h were determined by X-ray crystallographic
analysis.16
We were pleased to find that alkylketimines were also well
toleratedinthereaction(Scheme2),sincewewereconcernedthat
thesesubstrateswouldtautomerizetoenaminesinthepresenceof
potassium tert-butoxide. Several alkylketimines reacted to give
homopropargylic products in excellent er (5a−d). Furthermore,
we found that other functional groups are compatible with this
method: sultam 5c, containing an acetal protecting group, was
a
Enantiomeric ratio could not be determined using chiral SFC
instrumentation.
formed in high yield. The absolute configurations of 5b and 5c
were determined by X-ray crystallographic analysis.17
To emphasize the utility of the pendant terminal alkyne, we
synthesized derivatives of several alkyl and aryl homopropargylic
sulfonamides (Scheme 3). We prepared compound 5d for an
enyne ring-closing metathesis (Scheme 3a).18 Inthe presenceof 5
mol % of Grubbs I catalyst and under an atmosphere of ethylene,
the desired spirocycle 6 was obtained in 76% yield. The
Sonogashira cross-coupling reaction of compound 5b with ethyl
4-iodobenzoate proceeded in high yield (Scheme 3b). Lindlar
reduction of 3a provided the corresponding enantioenriched
diarylallylsultam8,amoietythathasnotbeenpreviouslyreported
(Scheme 3c).7e,19 We further highlighted the versatility of the
alkyne moiety by fully reducing 3a to alkane 9 in 89% yield using
palladium on carbon, without reduction of the cyclic benzylic
sulfonamide (Scheme 3d).
B
DOI: 10.1021/acs.orglett.5b02692
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Organic Letters
Letter
Scheme 4. Scope of Alkyl Sulfamidates
Table 2. Silver-Catalyzed Propargylation Reaction Using
Allenylboronic Acid Pinacol Ester 2 or Propargylboronic Acid
Pinacol Ester 12
a
b
c
1
Determined by H NMR. Isolated yield. Determined using chiral
d
SFC. Determined using 1H NMR by comparison to PhTMS as
internal standard.
allenyl borolane 2 or propargyl borolane 12 would result in
formation of alkyne 3a via equilibration of 13 and 14 (Figure 1a).
An alternative pathway is mechanism B, involving direct
additionoftheborolanereagenttotheketimine.20 Inthisscenario,
the silver catalyst acts as a chiral Lewis acid in the reaction (Figure
1b(1)).Coordinationofthesilvercatalysttoformintermediate16
followedbySE2′additionofallenylborolane2resultsinformation
of alkyne 3a. In this possible mechanism, isomerization of the
allenyl- and propargylboron species is slower than attack on the
activatedelectrophile(16).21 Therefore,usingpropargylborolane
12 would provide a different product, allene 18 (Figure 1b (2)).
Torule outoneofthesetwopossiblemechanisms, weset outto
examine reactions employing propargyl borolane 12.25 We
synthesized 12 using a procedure recently published by Fandrick
and co-workers.22c Using propargyl borolane 12 in the reaction
yielded alkyne 3a in 64% (Table 2).26 We found that the er of the
product remained high, with a slight decrease when using
propargyl borolane 12. To determine whether or not propargyl
borolane 12 is in equilibrium with allenyl borolane 2 under the
reaction conditions, the reaction was performed in deuterated
DMFandtheratioofpropargyltoallenylborolanewasanalyzedby
1H NMR before workup. The ratio of propargyl borolane 12 to
allenyl borolane 2 remained similar before and after the reaction,
most consistent with negligible equilibration of 12 and 2 over the
time course of the propargylation reactions. While other
mechanistic possibilities exist, these results are most consistent
with mechanism A, where the silver catalyst undergoes trans-
metalation with the borolane reagent.
Figure 1. Possible mechanisms for silver-catalyzed propargylation
reaction. (a) Proposed catalytic cycle involving transmetalation of silver
catalyst with borolane reagent. (b) Lewis acid catalysis.
Cyclic sulfamate ketimines (e.g., 10) are a related class of N-
sulfonylketimines that react with nucleophiles to provide
sulfamidates that can be easily transformed to 2-hydroxyphenyl-
methylamines.7 However, these ketimines are typically less
reactiveinadditionreactions.Wewantedtochallengeourmethod
and found that homopropargylic sulfamidates 11a and 11b were
formed in good yield and >99:1 er (Scheme 4).
We sought to establish a reasonable mechanism for this
propargylation reaction; two of the most likely possibilities are
presented in Figure 1.20 Our approach to distinguish between
these mechanisms was to compare product distributions from
reactions employing isomeric borolane reagents, allenyl borolane
2 and propargyl borolane 12. Importantly, both mechanisms take
into account our experimental observation that allenyl borolane 2
and propargyl borolane 12 are not in equilibrium under the
reaction conditions during the time frame of the reaction (vide
infra).21
MechanismAinvolvestransmetalationandisomerizationofthe
allenylmetalintermediates.22Transmetalationofthesilvercatalyst
with the borolane reagent forms the key nucleophilic allenylsilver
complex (13) in situ. Allenylsilver complex 13 is in equilibrium
with propargylsilver complex 14.23,24 Addition of allenylsilver
complex 13 to the ketimine via SE2′ mechanism is favored to form
alkyne 3a. Therefore, if mechanism A is operative, using either
In summary, we have developed an enantioselective silver-
catalyzed propargylation reaction of cyclic N-sulfonylketimines.
Using a catalyst prepared from AgPF6 and Walphos-1, we found
that many aryl and alkyl homopropargylic amines were formed in
high yield and excellent er. Derivatization of the terminal alkyne
yielded spirocyclic, alkenyl, or alkyl products. Mechanistic
experiments employing propargyl borolane reagent are most
consistentwithamechanisminwhichthesilvercatalystundergoes
transmetalation with the borolane reagent to generate a
nucleophilic allenylboron reagent.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.5b02692.
C
DOI: 10.1021/acs.orglett.5b02692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
X-ray crystallographic data for 3a (CIF)
Letter
propargylation reactions of ketones and imines, see: Wisniewska, H. M.;
Jarvo, E. R. J. Org. Chem. 2013, 78, 11629.
X-ray crystallographic data for 3f (CIF)
X-ray crystallographic data for 3h (CIF)
X-ray crystallographic data for 5b (CIF)
X-ray crystallographic data for 5c (CIF)
Experimental procedures and characterization data for all
new compounds (PDF)
(10) For catalyst-controlled, enantioselective propargylation of imines,
see:(a)Kagoshima, H.;Uzawa,T.;Akiyama, T.Chem. Lett.2002,31,298.
(b) Wisniewska, H. M.; Jarvo, E. R. Chem. Sci. 2011, 2, 807. (c) Vieira, E.
M.; Haeffner, F.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2012, 51, 6618.
(11) For examples of diastereoselective propargylation of imines, see:
(a)Gonzalez,A.Z.;Soderquist,J.A.Org.Lett.2007,9,1081.(b)Fandrick,
D. R.;Johnson, C. S.;Fandrick, K. R.;Reeves, J. T.;Tan, Z.;Lee, H.;Song,
J. J.; Yee, N. K.; Senanayake, C. H. Org. Lett. 2010, 12, 748. (c) García-
AUTHOR INFORMATION
Corresponding Author
■
Munoz, M. J.; Zacconi, F.; Foubelo, F.; Yus, M. Eur. J. Org. Chem. 2013,
̃
2013, 1287. (d) Guo, T.; Song, R.; Yuan, B.-H.; Chen, X.-Y.; Sun, X.-W.;
Lin,G.-Q.Chem.Commun.2013,49,5402.(e)Chen,D.;Xu,M.-H.Chem.
Commun. 2013, 49, 1327.
*E-mail: erjarvo@uci.edu.
Notes
The authors declare no competing financial interest.
(12)Kohn, B.L.;Ichiishi,N.;Jarvo, E. R.Angew. Chem., Int.Ed. 2013,52,
4414.
(13)Forsilver-catalyzedenantioselectiveallylationreactionsofketones,
see: Wadamoto, M.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 14556.
(14) Formation of silver phosphine complexes in methanol followed by
solvent replacement with THF is employed in related transformations.
See refs 10b 12, and 13.
ACKNOWLEDGMENTS
■
Thisworkwassupported byNIHNCI(F31CA177212 toC.A.O)
and DoEd GAANN (PA200A120070 to T.B.D.E). We thank Dr.
Daniel Fandrick (Boehringer Ingelheim) for helpful discussions
regarding the synthesis of propargylboronic acid pinacol ester 12.
Dr. Joseph Ziller and Jordan Corbey (University of California,
Irvine) are acknowledged for X-ray crystallography data. Dr. John
GreavesandDr.BeniamBerhane(UniversityofCalifornia,Irvine)
are acknowledged for mass spectrometry data.
(15) Kohn, B. L.; Jarvo, E. R. Org. Lett. 2011, 13, 4858.
(16) For supplementary crystallographic data, see the Supporting
Information and CCDC 1405841, 1405894, and 1405895.
(17) For supplementary crystallographic data, see the Supporting
Information and CCDC 1410049 and 1405843.
(18) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317.
(19) For enantioselective allylation of alkyl cyclic N-sulfonylketimines,
see: Hepburn, H. B.; Chotsaeng, N.; Luo, Y.; Lam, H. W. Synthesis 2013,
45, 2649.
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̈
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D
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Org. Lett. XXXX, XXX, XXX−XXX