Alternate mode of palladium-catalyzed alkynyliminium ion cyclizations affording stereodefined N-alkyl-3-alkylidenepyrrolidines

Article abstract of DOI:10.1021/ol402685g

Pd/P(c-C₆H₁₁)₃-catalyzed alkynyliminium ion cyclization in the presence of organoboronic acids affords stereodefined N-alkyl-3-alkylidenepyrrolidines. The distinctive cis-selective addition of the boronic acids and the imi

Full text of DOI:10.1021/ol402685g

ORGANIC
LETTERS
2013
Vol. 15, No. 23
5932–5935
Alternate Mode of Palladium-Catalyzed
Alkynyliminium Ion Cyclizations
Affording Stereodefined
N‑Alkyl-3-alkylidenepyrrolidines
Hirokazu Tsukamoto,* Mitsugu Shiraishi, and Takayuki Doi
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-aza aoba
6-3, Aoba-ku, Sendai 980-8578, Japan
hirokazu@mail.pharm.tohoku.ac.jp
Received September 19, 2013
ABSTRACT
Pd/P(c-C6H11)3-catalyzed alkynyliminium ion cyclization in the presence of organoboronic acids affords stereodefined N-alkyl-3-alkylidenepyrrolidines.
The distinctive cis-selective addition of the boronic acids and the iminium ions across the alkyne would result from favored 5-exo- or 6-exo-dig
cyclization through oxidative addition of the formaldiminium ions to Pd(0).
Transition-metal-catalyzed carbocyclization of alkynes
and alkenes is a powerful one-step method to prepare
biologically important carbo- and heterocycles.1 Carbocy-
clizations of alkynes bearing a carbonyl and related func-
tionality have received scattered attention because it was
believed that formation of π-complexes between the car-
bonꢀheteroatom π-bond and transition-metal catalysts
was unfavorable.2 However, these carbocyclizations can,
in fact, be accessed using organometallic reagents under
appropriate conditions. Their proposed reaction mechan-
isms are divided into the following three classes: (1) 1,2-
addition of the alkenylmetal intermediate, which is gener-
ated in situ by the regioselective alkyne insertion between
RꢀRh(I)3 or RꢀPd(II)4 bonds formed by transmetalation
(TM) to carbonꢀheteroatom multiple bonds (mechanism
A); (2) oxidative metallacycle formation with low-valent
transition metal catalysts such as Ni(0)5 and Pd(0)6 fol-
lowed by TM and reductive elimination (RE) (mechanism
B); (3) “anti-Wacker”-type oxidative addition7 to Pd(0)
and subsequent TM and RE, a method that was developed
by our group (mechanism C).8 In remarkable contrast to
the reactions proceeding through mechanisms A and B,
(4) (a) Tsukamoto, H.; Kondo, Y. Org. Lett. 2007, 9, 4227–4230. (b)
Yang, M.; Zhang, X.; Lu, X. Org. Lett. 2007, 9, 5131–5133. (c) Han, X.;
Lu, X. Org. Lett. 2010, 12, 108–111. (d) Wang, H.; Han, X.; Lu, X.
Tetrahedron 2010, 66, 9129–9134.
(5) (a) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119,
9065–9066. (b) Ni, Y.; Amarasinghe, K. K. D.; Montgomery, J. Org.
Lett. 2002, 4, 1743–1746. (c) Montgomery, J. Angew. Chem., Int. Ed.
2004, 43, 3890–3908 and references therein. For the synthesis of allylic
amines, see: (d) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003,
42, 1364–1367. (e) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed.
2004, 43, 3941–3944.
(6) Alkyne isocyanates allow the oxapalladacycle formation to
give 3-alkylideneoxindoles. Miura, T.; Toyoshima, T.; Takahashi, Y.;
Murakami, M. Org. Lett. 2008, 10, 4887–4889.
(7) Camacho, D. H.; Saito, S.; Yamamoto, Y. Tetrahedron Lett.
2002, 43, 1085–1088.
(8) Pd(0)-catalyzed carbocyclizations of alkyne-carbonyls. (a)
Tsukamoto, H.; Ueno, T.; Kondo, Y. J. Am. Chem. Soc. 2006, 128,
1406–1407. (b) Tsukamoto, H.; Ueno, T.; Kondo, Y. Org. Lett. 2007, 9,
3033–3036.
(1) (a) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem.
Rev. 1996, 96, 635–662. (b) Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev.
2010, 39, 2791–2805. (c) Sohel, S. M. A.; Liu, R.-S. Chem. Soc. Rev.
2009, 38, 2269–2281. (d) Zhang, D.-H.; Zhang, Z.; Shi, M. Chem.
Commun. 2012, 48, 10271–10279.
(2) (a) Vicente, J.; Abad, J.-A.; Gil-Rubio, J. J. Organomet. Chem.
1992, 436, C9–C12. (b) Quan, L. G.; Gevorgyan, V.; Yamamoto, Y.
J. Am. Chem. Soc. 1999, 21, 3545–3546. (c) Gevorgyan, V.; Quan, L. G.;
Yamamoto, Y. Tetrahedron Lett. 1999, 40, 4089–4092. (d) Larock,
R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc. 1999, 21, 3238–
3239. (e) Tian, Q.; Pletnev, A. A.; Larock, R. C. J. Org. Chem. 2003, 68,
339–347.
(3) (a) Okamoto, R.; Otomaru, Y.; Ueyama, K.; Hayashi, T. J. Am.
Chem. Soc. 2005, 127, 54–55. (b) Miura, T.; Murakami, M. Chem.
Commun. 2007, 217–224 and references therein.
r
10.1021/ol402685g
Published on Web 11/08/2013
2013 American Chemical Society

trans-selectivity observed in our carbocyclizations (through
mechanism C) enabled 6-endo-trig cyclization of alkynyl
iminium ions 4 generated in situ from but-3-ynylamines
1 and formaldehyde leading to 1,4-disubstituted 1,2,3,6-
tetrahydropyridines 3 in the presence of organoboronic
acids 2 (Scheme 1).9
products (3aA, 70aA) were observed. We were intrigued by
this result and motivated to investigate cis-selective arylative
cyclization in detail. To the best of our knowledge, this is the
first report on cis-selective alkyneꢀiminium ion cyclization.
Scheme 2. Unexpected Cis-Selective Arylative Cyclization of 1a
with 2A
Scheme 1. Pd(0)-Catalyzed Alkynyliminium Ion Cyclizations
Leading to Tetrahydropyridine 3 and Pyrrolidine 7
The cis-selective arylative cyclization of 1b with 2A
required the presence of phosphine ligands containing at
least one cyclohexyl group and the (η3-allyl)PdCp catalyst
(Table 1, entries 1ꢀ4). More σ-donating and sterically
demanding tri-tert-butylphosphine and diphosphine were
ineffective (entries 5 and 6). As expected, a substitution of
(η3-allyl)PdCp by Ni(cod)2 afforded no cyclization pro-
duct, and the absence of catalyst led to Petasis boronic
acidꢀMannich reaction15 and N-methylation16 (data not
shown).17 The minimal side reactions observed at 80 °C
could be prevented by lowering the reactiontemperature to
50 °C affording 7bA in slightly higher yield (entries 4 vs 7).
Among the solvents we tested, ethereal solvents including
1,2-dimethoxyethane (DME) and 1,4-dioxane (DOX)
proved best (entries 7ꢀ10). With the optimized reaction
conditions in hand, we examined the cyclization of 1b with
a wide variety of boronic acids.
The carbocyclization was compatible with ortho-
substitution in the boronic acids (Table 2, entries 1 and 2).
In contrast to the Pd(PPh3)4-catalyzed arylative cyclization
of alkynyl iminium ions, unsubstituted- (2D) and electron-
withdrawing group substituted (2E,F) phenylboronic acids
did not retard the cyclization and gave 7bDꢀF in good
yields under the same reaction conditions (entries 3ꢀ5).
Ketone and ester functionalities were also tolerated. Both
electron-rich (2G,H) and electron-deficient (2I,J) heteroaryl
boronic acids participated in the cyclization (entries 6ꢀ9).
The cyclization reaction also took place with alkenylboronic
acid 2K to provide the 1,3-diene 7bK (entry 10).
Despite their utility for diversity-oriented synthesis,10
catalysts that promote the transformation of iminium 4
(or the corresponding imine of 1) into a 5-membered
heterocycle (i.e., pyrrolidine 7) in either cis or trans fashion
have not been found. The difficulty in accessing 7 has been
ascribed to a disfavored 5-endo-trig cyclization through
mechanisms A or C.11ꢀ13 Thus, alternative reaction con-
ditions to realize this transformation are needed.14
We endeavored to expand the scope of the Pd(0)-
catalyzed three-component coupling reaction between but-
3-ynylamines 1, arylboronic acids 2, and formaldehyde. We
were surprised to discover that when amine 1a, containing
internal alkyne functionality, was subjected to trans-
selective cyclization with p-methoxyphenylboronic acid
(2A), the expected product, tetrahydropyridine 3aA, was
not observed (Scheme 2). Although no reaction took place
with triphenylphosphine ligand, cyclization of 1a was
achieved with addition of the more σ-donating tricyclo-
hexylphosphine ligand. This ligand was previously shown
to be effective in trans-selective alkylative cyclizations of
iminium ions derived from alk-4-ynals and external sec-
ondary amines.8b Surprisingly, NMR experiments on our
cyclization product established its structure as pyrrolidine
7aA resulting from cis-addition, while no trans-addition
(9) Pd(0)-catalyzed carbocyclizations of alkyneꢀ and alleneꢀ
iminium ions: Tsukamoto, H.; Kondo, Y. Angew. Chem., Int. Ed.
2008, 47, 4851–4854.
(10) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43,
46–58.
(11) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736.
(12) Nucleophile-promoted cyclizations of but-3-ynylamines occur
in the endocyclic sense to afford 1,4-disubstituted 1,2,3,6-tetrahydro-
pyridines: (a) Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 1988, 110,
612–614. (b) Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 1988, 110,
5934.
A secondary alkyl group on the nitrogen atom was also
tolerated for the cyclization (Table 3, entry 3). The pre-
sence of an electron-donating methoxy group at the para-
position to the ethynylbenzene in 1f (entry 5) retarded the
reaction, relative to entries 4 and 6, but good product yield
(15) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445–
446.
(13) It is reported that propargylsilanes undergo 5-endo-trig cycliza-
tion with iminium ions generated in situ to give 3-vinylidene-N-alkyl-
pyrrolidines under acidic conditions against Baldwin’s rule: Damour,
D.; Pornet, J.; Miginiac, L. Tetrahedron Lett. 1987, 28, 4689–4690.
(14) 5-Exo-dig cyclization should be an alternative mode. Oxidative
addition of carbamoyl chlorides and cyanoformamides to Pd(0) and the
following alkyne insertion is used to prepare 3-alkylideneoxindoles. (a)
Fielding, M. R.; Grigg, R.; Urch, C. J. Chem. Commun. 2000, 2239–
2240. (b) Kobayashi, Y.; Kamisaki, H.; Yanada, R.; Takemoto, Y. Org.
Lett. 2006, 8, 2711–2713.
(16) Formic acid generated in situ by disproportion of formaldehyde
may cause EschweilerꢀClarke methylation. An acid catalyst is reported
to promote the disproportion: Ogorodnikov, S. K.; Filippova, V. A.;
Blazhin, Y. M.; Vergunova, N. G.; Svetlova, L. M.; Mamontova, N. I.
Khim.-Farm. Zh. 1987, 21, 862–866.
(17) Additionally, substitution of aqueous formaldehyde by paraf-
ormaldehyde and boronic acid by its neopentylglycol ester did not give
better results.
Org. Lett., Vol. 15, No. 23, 2013
5933

Table 1. Ligand and Solvent Effects on Arylative Cyclization of
1b with 2A
Table 3. Substituent Effects on Arylative Cyclization of 1aꢀj
with 2A or 2Fa
entry
R1
R2
7
time (h) yield (%)
1
PMB
Ph
Ph
Ph
Ph
7aA
7cA
7dA
7eA
7fA
15
24
15
3
90
61
65
72
90
83
57
42
67d
40e
entry
ligand
solventa temp (°C) time (h) yield (%)
2
n-C4H9
i-C3H7
Bn
1
2
3
4
5
6
7
8
9
10
PPh3
PPh2(c-C6H11
PPh(c-C6H11 2
P(c-C6H11 3
THF
THF
THF
THF
THF
THF
THF
DMF
DOX
DME
80
80
80
80
80
80
50
50
50
50
4
1
traceb
71b
71b
61b
0
3
4b
5
)
)
1
Bn
p-MeOC6H4
p-NO2C6H4
13
3
6b
7c
8c
9
Bn
7gA
)
2
P(t-Bu)3
dppec
6
p-MeC6H4CH2 1-cyclohexenyl 7hA
24
24
12
12
6
0
p-MeC6H4CH2 n-C4H9
7iA
7jA
7jF
P(c-C6H11 3
P(c-C6H11 3
P(c-C6H11 3
P(c-C6H11 3
)
18
6
68
Bn
Bn
H
H
)
68
10
)
13
13
84
a Reaction with 2A and 2F for entries 1ꢀ9 and 10, respectively.
)
91
b Reaction in DME instead of DOX. c Reaction with PPh(c-C6H11 2
)
instead of P(c-C6H11)3. d Combined yields with trans-addition product
3jA (7jA:3jA = 5:1, ratio determined by 1H NMR analysis). e Combined
yields with trans-addition product 3jF (7jF:3jF = 30:1, ratio determined
by 1H NMR analysis).
a THF, DMF, DOX, and DME stand for tetrahydrofuran, N,N-
dimethylformamide, 1,4-dioxane, and 1,2-dimethoxyethane, respectively.
b Small amounts of byproducts resulting from Petasis boronic acidꢀ
Mannich reaction and N-methylation were also observed. c dppe = 1,2-
bis(diphenylphosphino)ethane.
Tether effects on the cyclizations of but-3-ynylamines
1kꢀn were briefly explored (Table 4). Although the aryla-
tivecyclization of trans-2-(phenylethynyl)cyclohexylamine
1k was less efficient than its cis-isomer (1b), the cis-
cyclopentyl homologue 1l underwent the cyclization as
efficiently (entries 1 and 2). More flexible tethers in but-3-
ynylamines 1m and 1n reduced the product yields (entries 3
and 4). In addition, the corresponding primary amine,
N-alkyl-2-(phenylethynyl)aniline, and aldehydes except for
formaldehydegavenocyclizationproduct, whichsuggested
that the N,N-dialkylformaldiminium ions generated in situ
should be a key intermediate for the cyclization (data not
shown).
Table 2. Cyclization of 1b with Aryl-, Heteroaryl-, and
Alkenylboronic Acids 2BꢀK
entry
R in 2
7
time (h)
yield (%)
1
o-MeOC6H4 2B
o-MeC6H4 2C
7bB
7bC
7bD
7bE
7bF
7bG
7bH
7bI
16
16
24
16
2
88
79
85
66
78
84
66
66
51
88
A
plausible mechanism for the Pd/P(c-C6H11)3-
2
3
C6H5 2D
catalyzed cis-selective arylative cyclization of alkynyl for-
maldiminium ions generated from 1 is shown in Scheme 3.
According to the reported regioselectivities of the
carbometalation of phenyl-substituted alkynes,2,4 5-endo-
trig cyclization through mechanism A is unlikely.19 The
ThorpeꢀIngold effect20 should play an important role to
set the alkyne-coordinated Pd toward formaldiminium ion
8, while σ-donating tricyclohexylphosphine ligand would
allow oxidative addition of the iminium to Pd(0)21 leading
4
p-MeO2CC6H4 2E
p-AcC6H4 2F
5a
6a
7
2-thiophene 2G
3-thiophene 2H
2-methoxy-3-pyridyl 2I
6-methoxy-3-pyridyl 2J
(E)-β-styrene 2K
13
17
17
17
3
8
9
7bJ
7bK
10
a Reaction in DOX instead of DME.
was maintained. Employment of PPh(c-C6H11)2 as ligand
gave better results when alkenyl or alkyl groups are sub-
stituted on the alkyne terminus to give 7hA and 7iA in
moderate yields (entries 7 and 8). Using either electron-rich
or -deficient arylboronic acids, amine 1j, containing a
terminal alkyne, was cyclized under Pd/P(c-C6H11)3 cata-
lysis to give pyrrolidine 7jA and 7jF as major products
(entries 9 and 10).18 This result suggests that the alkyne
substituent is not essential for the cis-selective cyclization.
(18) In contrast to the cyclization of internal alkyne 1b, use of PPh3,
PPh2(c-C6H11), and PPh(c-C6H11)2 as ligands resulted in the conversion
of 1j to tetrahydropyridines 3j as major products. The ratios of 7j to 3j
slightly increase as cyclohexyl groups substitute phenyl groups in the
phosphine ligands.
(19) Pd(OAc)2(dppe), reported to be an appropriate catalyst for the
reaction mechanism A, was ineffective for this cyclization.
(20) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735–1766.
(21) A combination of (η3-allyl)PdCp with an excess of phosphine
ligand is known to produce phosphine-ligated Pd(0) species accompa-
nied with reductive elimination of 5-allylcyclopenta-1,3-diene: Tatsuno,
Y.; Yoshida, T.; Otsuka, S. Inorg. Synth. 1979, 19, 220–223.
5934
Org. Lett., Vol. 15, No. 23, 2013

Table 4. Substrate Scope and Limitations
Scheme 3. Plausible Mechanism for the Arylative Cyclization of 1
carbopalladation and TM would be interchangeable (9 f
13 f 11 f 7). The diorganopalladium(II) intermediate
13 may also be formed by TM between 2 and Pd(II)ꢀ
CH2ꢀN three membered ring 12,22,24 which would be in
equilibrium to (η2-formaldiminium)Pd(0) complex 8 as
well as 9. Alternative alkyne insertion between the ArꢀPd
bond in 13 followed by reductive elimination of 7 from
palladacycle 14 is also possible.
a Reaction in DOX. b Reaction in DME. c Reaction with 10 mol % of
catalysts.
This study has uncovered the first example of a cis-
selective alkyneꢀiminium ion cyclization leading to N-alkyl-
3-alkylidenepyrrolidines. We have previously reported that
similar reaction conditions afford tetrahydropyridines.9
We now show that by simply varying the phosphine
ligands for the Pd catalyst two diverse product scaffolds
(tetrahydropyridines and pyrrolidines) can be obtained.
Stereodefined tri- and tetrasubstituted olefins in the products
can be further functionalized leading to highly complex
heterocycles. The proposed cyclization mechanism, proceed-
ing by oxidative addition of iminium ions to Pd(0), should be
useful for devising methods to access other difficult organic
transformations. Studies to elucidate more mechanistic
details and expand the scope of the cyclization process are
underway.
to aminomethylpalladium(II) 9.22,23 Either the less
σ-donating triphenylphosphine-ligated Pd(0) or a substi-
tuted formaldiminium ion would retard this oxidative
addition step. Subsequent insertion of the coordinated
alkyne between the carbonꢀPd bond in 9 would provide
alkenylpalladium(II) 10, which undergoes TM with aryl-
boronic acid 2 and RE to give pyrrolidine 7 and Pd(0). An
electron-withdrawing aryl-substituted alkyne would be-
come susceptible to both coordination to the electron-
rich Pd(0) and carbopalladation processes. The order of
(22) Although Pdꢀ(η2-iminium) complexes like 9 and 12 have not, to
our knowledge, been prepared by oxidative addition of the iminium ions
to Pd(0), it can be prepared by activation of a CꢀH bond adjacent to the
amine N-atom in trialkylamines with a Pd(II) complex: Lu, C. C.; Peters,
J. C. J. Am. Chem. Soc. 2004, 126, 15818–15832.
Acknowledgment. This work was partly supported by
a Grant-in-Aid from the Japan Society for Promotion
of Sciences (No.24590004), The Research Foundation
for Pharmaceutical Sciences, and the Suntory Foundation
for Life Sciences.
(23) It is reported that oxidative addition of N-acyliminium ion to
Pd(0) and Ni(0) gives a metal-chelated amide complex: (a) Dghaym,
R. D.; Dhawan, R.; Arndtsen, B. A. Angew. Chem., Int. Ed. 2001, 40,
3228–3230. (b) Dhawan, R.; Dghaym, R. D.; Arndtsen, B. A. J. Am.
Chem. Soc. 2003, 125, 1474–1715. (c) Davis, J. L.; Dhawan, R.;
Arndtsen, B. A. Angew. Chem., Int. Ed. 2004, 43, 590–594. (d) Lu, Y.;
Arndtsen, B. A. Org. Lett. 2007, 9, 4395–4397. (e) Siamaki, A. R.; Black,
D. A.; Arndtsen, B. A. J. Org. Chem. 2008, 73, 1135–1138. (f) Graham,
T. J. A.; Shields, J. D.; Doyle, A. G. Chem. Sci. 2011, 2, 980–984.
(24) (Ph3P)Ni(H2CdNMe2)Cl, prepared by oxidative addition of
(H2CdNMe2)Cl to Ni(0) complexes, i.e., (Ph3P)2Ni(C2H4) or
(Ph3P)4Ni, undergoes a substitution reaction with cyclopentadienyl
anion to give (Ph3P)Ni(CH2NMe2)Cp, which contains a dimethylami-
nomethyl group σ-bonded to nickel: Sepelak, D. J.; Pierpont, C. G.;
Barefield, E. K.; Budz, J. T.; Poffenberger, C. A. J. Am. Chem. Soc. 1976,
98, 6178–6185.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 23, 2013
5935