Stereoselective vinylation of aryl n-(2-pyridylsulfonyl) aldimines with 1-alkenyl-1,1-heterobimetallic reagents

Article abstract of DOI:10.1021/ol202766g

Vinylation of aryl N-(2-pyridylsulfonyl) aldimines with versatile 1-alkenyl-1,1-borozinc heterobimetallic reagents is disclosed. In situ hydroboration of air-stable B(pin)-alkynes followed by chemoselective transmetalation with dimethylzinc and addition t

Full text of DOI:10.1021/ol202766g

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6464–6467
Stereoselective Vinylation of Aryl
N-(2-Pyridylsulfonyl) Aldimines with
1-Alkenyl-1,1-heterobimetallic Reagents
Nusrah Hussain, Mahmud M. Hussain, Muhammed Ziauddin,
Plengchat Triyawatanyu, and Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, University of Pennsylvania, Department of
Chemistry, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323,
United States
pwalsh@sas.upenn.edu
Received October 14, 2011
ABSTRACT
Vinylation of aryl N-(2-pyridylsulfonyl) aldimines with versatile 1-alkenyl-1,1-borozinc heterobimetallic reagents is disclosed. In situ hydroboration
of air-stable B(pin)-alkynes followed by chemoselective transmetalation with dimethylzinc and addition to aldimines provides B(pin)-substituted
allylic amines in 53ꢀ93% yield in a one-pot procedure. The addition step can be followed by either BꢀC bond oxidation to provide R-amino
ketones (71ꢀ98% yield) or Suzuki cross-coupling to furnish trisubstituted 2-arylated (E)-allylic amines (51ꢀ73% yield).
Highly stereoselective construction of CꢀC double
bonds remains a challenge in organic synthesis.1 In this
regard, sp3 and sp2 hybridized heterobimetallic reagents of
Scheme 1. 1,1-Heterobimetallics in Organic Synthesis
type I and II (Scheme 1) are potentially useful intermedi-
ates, because each metalꢀcarbon bond can be chemoselec-
tively exploited in CꢀC bond forming reactions.2ꢀ4,6
Furthermore, these versatile heterobimetallic reagents
can be employed in tandem reactions, minimizing isolation
(1) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis;
John Wiley & Sons: New York, 1988.
(2) Marek, I.; Normant, J. -F. Chem. Rev. 1996, 96, 3241.
(3) (a) Marek, I. Chem. Rev. 2000, 100, 2887. (b) Marek, I. Actual.
Chim. 2003, 15.
(4) Waas, J. R.; Sidduri, A.; Knochel, P. Tetrahedron Lett. 1992, 33,
3717.
(5) (a) Ho, T. L. Tandem Organic Reactions; Wiley and Sons:
New York, 1992; p 502. (b) Wender, P. A.; Miller, B. L. Organic Synthesis:
Theory and Applications; Hudlicky, T., Ed.; JAI Press: Greenwich, CT, 1993;
Vol. 2, p 27. (c) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996,
96, 195. (d) Schmalz, H.-G.; Geis, O. Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley: New York, 2002;
Vol. 2, p 2377. (e) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem.
Commun. 2003, 551. (f) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed.
1993, 32, 131. (g) Walsh, P. J.; Kozlwoski, M. C. Fundamentals of
Asymmetric Catalysis; University Science Books: Sausalito, CA, 2008.
(6) Hussain, M. M.; Walsh, P. J. Acc. Chem. Res. 2008, 41, 883.
and purification of intermediates.5 These attributes allow
for rapid development of molecular complexity from
simple building blocks.
As part of our program in developing stereoselective
CꢀC bond forming reactions,6 we have reported the
generation of 1-alkenyl-1,1-heterobimetallic reagents
r
10.1021/ol202766g
Published on Web 11/15/2011
2011 American Chemical Society

based on boron and zinc from readily available, air-stable
B(pin)-substituted alkynes (Scheme 2).7a Thus, regioselec-
tive hydroboration of B(pin)-alkynes generates the 1,1-bis
(boro) intermediates.7a,8 Chemoselective transmetalation
of the more reactive vinyl-BCy2 bond generates 1-alkenyl-
1,1- heterobimetallic reagents. The difference in reactivity
between ZnꢀC vs BꢀC bonds allows for selective reaction
at the ZnꢀC bond with aldehydes to yield B(pin)-substi-
tuted allylic zinc alkoxide intermediates. The alkoxide
intermediates were then employed in various tandem
reactions to form an array of compounds such as B(pin)-
substituted allylic alcohols,7aꢀc R-hydroxy ketones,7a tri-
substituted (E)-allylic alcohols,7a B(pin)-substituted cyclo-
propyl alcohols,7b and B(pin)-substituted allylicacetates.7d
to aldimines activated with a diphenylphosphinoyl moiety
(Scheme 3).13 Carretero14 and co-workers demonstrated
that the reactivity of N-sulfonyl imines could be increased
in the presence of an appropriately positioned heteroaryl
group. Using this strategy, they developedthe alkylationof
aryl N-(2-pyridylsulfonyl) aldimines with organozinc
halides.14b The Carretero and Toru groups both have
utilized the N-pyridylsulfonyl as a novel stereocontrol
element in enantioselective Mannich-type reactions with
silyl enol ethers in the presence of chiral copper catalysts.15
Various related nucleophilic reagents, such as dialkyl
zinc,5,16,17 alkynylzinc,5,18 diethylaluminium cyanide,19
and Danishefsky’s diene,20 have also been investigated in
imine addition reactions to yield the desired amines.
Scheme 2. Generation of 1-Alkenyl-1,1-heterobimetallics of
Boron/Zinc and Additions to Electrophiles
Scheme 3. Wipf’s Vinylation of Aryl Diphenylphosphinoyl
Imines via Vinylzinc Reagents
Our first task in the addition of bimetallics to imines was
to find a suitable imine activating group. The bimetallic
reagent was generated and allowed to react with activated
imines at ꢀ18 °C (Table 1). N-Tosylimines gave a trace
addition product with our alkenyl heterobimetallic re-
agents (entry 1). Rather, a significant amount of reduction
product was isolated. The N-Boc imine behaved similarly,
failing to furnish the desired amine (entry 2). When the
activatinggroupwas changedtodiphenylphosphinoyl, less
than 30% of the allylic amine was isolated. Gratifyingly,
the bimetallic addition to N-pyridyl sulfonyl imine oc-
curred smoothly in 73% yield in toluene at ꢀ18 °C to
furnish the desired product (entry 4). The addition
was then optimized with the N-pyridyl sulfonyl imines.
Switching the solvent from toluene to dicholoromethane
improved the yields slightly (entry 4 vs 7), while, in
THF, almost no product was formed (entry 5). Dimethylzinc
performed better than diethylzinc (entry 7 vs 9). Increasing
the reaction temperature from ꢀ18 to ꢀ10 °C led to a
diminished yield (entry 6 vs 7). With the optimized condi-
tions in entry 7, the scope of the reaction was examined.
Aryl aldimines with electron-donating or -withdrawing
groups were good substrates, providing the B(pin)
Herein, we report the addition of alkenyl-1,1- hetero-
bimetallic reagents to N-(2-pyridylsulfonyl) aldimines to
furnish B(pin)-substituted allylic amines (Scheme 2, lower
part). The addition can be followed by oxidation of the
BꢀC bond to provide R-aminoketones or by Suzuki cross-
coupling to provide densely functionalized trisubstituted
(E)-allylic amines.
Allylic amines9 are important pharmacophores that
can exhibit significant biological properties. Examples
include Acrivastine (Semprex),10 Flunarizine,11 and several
GABA uptake inhibitors.12 As a result, additions to imines
have attracted considerable attention. For example, Wipf
and co-workers reported the addition of vinylzinc reagents
(7) (a) Li, H.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130,
ꢀ
3521. (b) Hussain, M. M.; Li, H.; Hussain, N.; Urena, M.; Carroll, P. J.;
Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 6516. (c) Hussain, M. M.;
ꢀ
Hernandez-Toribio, J.; Carroll, P. J.; Walsh, P. J. Angew. Chem., Int. Ed.
2011, 50, 6337. (d) Hussain, M. M.; Walsh, P. J. Angew. Chem., Int. Ed.
2010, 49, 1834.
(8) Srebnik, M. Tetrahedron Lett. 1991, 32, 2449.
(9) (a) Kovacic, P. Med. Hypotheses 2007, 69, 1105. (b) Kovacic, P.
Med. Hypotheses 2006, 67, 151.
ꢀ
ꢀ
(15) (a) Gonzalez, A. S.; Arrayas, R. G.; Carretero, J. C. Org. Lett.
2006, 8, 2977. (b) Nakamura, S.; Sano, H.; Nakashima, H.; Kubo, K.;
Shibata, N.; Toru., T. Tetrahedron: Asymmetry 2007, 48, 5565.
(10) (a) Martın, V. S.; Woodward, S. S.; Katsuki, T.; Yamada, Y.;
´
Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237. (b) Slater,
J. W.; Zechnich, A. D.; Haxby, D. G. Drugs 1999, 57, 31.
(11) (a) Straub, H.; Koehling, R.; Speckmann, E. J. Brain Res. 1994,
658, 119. (b) Ashton, D.; Reid, K.; Willems, R.; Marrannes, R.;
Wauguier, A. Drug Develop. Res. 1986, 8, 396.
(12) Gibson, J. R.; Manna, V. K.; Salisbury, J. J. Int. Med. Res. 1989,
17, 28.
(13) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc.
2003, 125, 761.
^ ꢀ
(16) Charette, A. B.; Boezio, A. A.; Cote, A.; Moreau, E.; Pytkowicz,
J.; Desrosiers, J. -N.; Legault, C. Pure Appl. Chem. 2005, 77, 1259.
(17) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L.
J. Am. Chem. Soc. 2001, 123, 984.
(18) Zani, L.; Alesi, S.; Cozzi, P. G.; Bolm, C. J. Org. Chem. 2006, 71,
1558.
(19) Nakamaru, S.; Sato, N.; Sugimoto, M.; Toru, T. Tetrahedron:
Asymmetry 2004, 15, 1513.
ꢀ
(14) (a) Esquivias, J.; Arrayas, R. G.; Carretero, J. C. J. Org. Chem.
ꢀ
ꢀ
ꢀ
ꢀ
(20) Mancheno, O. G.; Gonzalez, A. S.; Arrayas, R. G.; Carretero,
2005, 70, 7451. (b) Esquivias, J.; Arrayas, R. G.; Carretero, J. C. Angew.
Chem., Int. Ed. 2006, 45, 629.
J. C. J. Am. Chem. Soc. 2004, 126, 456.
Org. Lett., Vol. 13, No. 24, 2011
6465

aromatic or aliphatic substituents (R = aryl, alkyl). Even
the bulky tert-butyl-substituted B(pin) alkyne underwent
addition to generate the corresponding allylic amine
in 60% yield (entry 5). Substitution at the ortho position
of the aldimine resulted in a slightly lower yield (entry 7 vs
3ꢀ5).
Table 1. Optimization of the Addition of Alkenyl-1,
1-heterobimetallics to N-Pyridyl Sulfonyl Imines
Having established vinylation of aldimines with our
heterobimetallics, we sought to examine tandem reactions
involving the BꢀC bond. Two such reactions are BꢀC
bond oxidation and Suzuki cross-coupling.
Weenvisionedthatoxidationof the2-B(pin)-substituted
allylic amines would provide access to valuable R-amino
ketones, which have important biological activity.21 In the
entry
R200Zn
solvent
R
yield (%)a
1
2
3
4
5
6
7
8
9
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Et2Zn
Et2Zn
toluene
toluene
toluene
toluene
THF
SO2Tol
trace
trace
<30
73
Boc
presence of NaBO3 H2O22 in THF/H2O (1:1) at rt, B(pin)-
P(O)Ph2
SO2(2-Py)
SO2(2-Py)
SO2(2-Py)
SO2(2-Py)
SO2(2-Py)
SO2(2-Py)
3
substituted allylic amines were smoothly oxidized to the
corresponding R-amino ketones in 71ꢀ98% yield (Table 3).
trace
68b
80
CH2Cl2
CH2Cl2
toluene
CH2Cl2
64
65
Table 3. Oxidation of Allylic Amines to R-Amino Ketones
a Isolated yields. b Reaction performed at ꢀ10 °C.
Table 2. Addition of Alkenyl-1,1-hetrobimetallics to N-Pyridyl
Sulfonyl Imines
a Isolated yields.
a Isolated yields.
(21) (a) Hanada, M.; Sugawara, K.; Koko, K.; Toda, S.; Nishiyama,
Y.; Tomita, K.; Yamamoto, H.; Konishi, M.; Oki, T. J. Antibiot. 1992,
45, 1746. (b) Soaresa, C. O.; Alvesa, M. J. M.; Becharaa, E. J. H. Free
Radic. Med. 2011, 50, 1760.
(22) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. Tetrahedron
Lett. 1989, 30, 1483.
substituted allylic amines in 53ꢀ93% yield (Table 2).
The air-stable B(pin)-substituted alkynes can contain
6466
Org. Lett., Vol. 13, No. 24, 2011

Scheme 4. Tandem Addition/BꢀC Bond Oxidation To Yield
R-Amino Ketone 2a
Scheme 5. Suzuki Cross-Coupling of Allylic Amines
The addition/oxidation reaction can also be executed in a
tandem fashion. Thus, after completion of the bimetallic
addition to the aldimine, the reaction mixture was sub-
Scheme 6. Removal of the 2-Pyridyl Sulfonyl Group followed by
Boc-Protection
jected to NaBO3 H2O to provide the R-amino ketone in
68% yield in one pot (Scheme 4).
3
We next utilized the BꢀC bond in Suzuki cross-coupling
reactions. In the presence of Pd(OAc)2 (15 mol %), PPh3
(30 mol %), Cs2CO3 (3 equiv), and aryl bromide (3 equiv)
in THF/H2O (10:1) at 75 °C, the B(pin)-substituted allylic
amines smoothly underwent cross-coupling to furnish the
2-arylated trisubstituted (E)-allylic amines in 51ꢀ73%
yield (Scheme 5). No (Z)-double bond isomers were ob-
served in these reactions.
Although the 2-pyridyl sulfonyl group is essential for the
addition step, its removal is important for applications of
the products. The 2-pyridyl sulfonyl group was readily
cleaved on treatment of 1a with magnesium in MeOH to
liberate the free amine 4 (Scheme 6).23,24 The free amine 4
was then transformed into its Boc-derivative 5 on treat-
ment with Boc2O at rt in 88% overall yield (Scheme 6).
In summary, the nucleophilic addition of 1-alkenyl-1,1-
borozinc heterobimetallic reagents to aryl N-(2-pyridyl-
sulfonyl) aldimines has been developed. This protocol
provides a variety of B(pin)-substituted allylic amines in
good yields. The addition step can be followed by a tandem
oxidative cleavage of the BꢀC bond to furnish valuable
R-amino ketones or by Suzuki cross-coupling to form
2-arylated trisubstituted (E)-allylic amines. It is noteworthy
that 2-arylated trisubstituted (E)-allylic amines are not
currently accessible via the TsujiꢀTrost reaction, because
2-arylated allylic acetates are not good substrates for the
allylic substitution reaction.7d Given that amino ketones
and allylic amines are important pharmacophores,10ꢀ12,21
we anticipate that the methods described herein will be
useful to the synthetic community.
Acknowledgment. We acknowledge the NIH (NIGMS
GM58101) and the NSF (CHE-0848467). Funds for in-
strumentation were provided by the NIH for an MS
(1S10RR023444). M.M.H. thanks the University of
Pennsylvania SAS for a Dissertation Completion Fellowship.
Supporting Information Available. Procedures and full
characterization of new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(23) Pak, C. S.; Lim, D. S. Synth. Commun. 2001, 31, 2209.
ꢀ
(24) Arrayas, R. G.; Cabrera, S.; Carretero, J. C. Org. Lett. 2005, 7,
219.
Org. Lett., Vol. 13, No. 24, 2011
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