Regioselective and diastereoselective aminoarylation of 1,3-dienes

Article abstract of DOI:10.1039/c4sc01152j

The 1,4-functionalization of dienes is a synthetically useful strategy for incorporating molecular complexity into a class of simple substrates. We report the aminoarylation of acyclic and cyclic 1,3-dienes via the sequential [4 + 2] cycloaddition with a sulfurdiimide reagent and copper-catalyzed allylic substitution with Grignard reagents. The regioselective and diastereoselective aminoarylation of unsymmetrical dienes is also presented, which highlights the utility of this method for generating products with multiple functional groups and stereocenters. This journal is

Full text of DOI:10.1039/c4sc01152j

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Regioselective and diastereoselective
aminoarylation of 1,3-dienes†
Cite this: Chem. Sci., 2014, 5, 4863
*
Hongli Bao, Liela Bayeh and Uttam K. Tambar
The 1,4-functionalization of dienes is a synthetically useful strategy for incorporating molecular complexity
into a class of simple substrates. We report the aminoarylation of acyclic and cyclic 1,3-dienes via the
sequential [4 + 2] cycloaddition with a sulfurdiimide reagent and copper-catalyzed allylic substitution
with Grignard reagents. The regioselective and diastereoselective aminoarylation of unsymmetrical
dienes is also presented, which highlights the utility of this method for generating products with multiple
functional groups and stereocenters.
Received 18th April 2014
Accepted 13th August 2014
DOI: 10.1039/c4sc01152j
www.rsc.org/chemicalscience
reagents and a sulfurdiimide reagent. We also present examples
of regioselective and diastereoselective aminoarylation. This
Introduction
process represents the rst example of selectively converting
simple 1,3-dienes into internal Z-olens that are functionalized
with aryl rings and sulfonamide.
The difunctionalization of 1,3-dienes is a powerful approach for
installing two functional groups into an inexpensive and
abundant class of hydrocarbons.1 Efficient methods have been
developed for the incorporation of two equivalents of the same
nucleophile (e.g., diamination2 and dialkylation,3 Scheme 1). In
contrast, selective difunctionalization with two distinct func-
tional groups, such as carbon-based and nitrogen-based groups,
remains rare.4 Major challenges in the development of this type
of transformation include: (1) selectivity for carboamination
over diamination or dialkylation, and (2) regioselectivity and
diastereoselectivity in the functionalization of unsymmetrical
dienes.
To address the aforementioned challenges in functionaliz-
ing dienes with two different functional groups, we envisioned a
novel strategy that was based on the unique reactivity of sul-
furdiimide 2 with unsaturated hydrocarbons (Scheme 2).5 Our
lab recently developed methods for the sulfurdiimide-mediated
selective functionalization of terminal olens with either
carbon- or nitrogen-based groups.6 We hypothesized that this
reaction manifold would enable the simultaneous functionali-
zation of 1,3-dienes, another class of unsaturated hydrocar-
bons, with carbon- and nitrogen-based groups through an
unprecedented aminoarylation process.
Herein, we describe a general method for the regioselective
1,4-aminoarylation of cyclic and acyclic dienes with Grignard
Diene 1 would undergo spontaneous oxidation by sulfurdii-
mide 2 to generate [4 + 2] adduct 3. Under properly selected
conditions, sulnamide 3 could be susceptible to metal-cata-
lyzed allylic alkylation with aryl Grignard reagents.7 The
Scheme 1 Selective difunctionalization of 1,3-dienes.
The University of Texas Southwestern Medical Center at Dallas, Department of
Biochemistry, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, USA. E-mail:
Uttam.Tambar@utsouthwestern.edu; Fax: +1-214-648-8856; Tel: +1-214-648-0580
† Electronic supplementary information (ESI) available. CCDC 1020077. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4sc01152j
Scheme 2 Aminoarylation of 1,3-dienes via sulfinamide 3.
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regioselectivity of the initial [4 + 2] cycloaddition and the a- 9 : 1 a-selectivity (entry 12). The product was generated with
selectivity of the subsequent Grignard coupling would establish exclusive Z-olen stereochemistry, which was a consequence of
a selective difunctionalization of unsymmetrical dienes.
the preservation of olen geometry in cycloadduct 6. Although
there are some reports of preserving olen geometry in copper-
mediated allylic alkylations,10 potential for olen isomerization
exists due to the rapid equilibration between p-allyl Cu(III) and
s-allyl Cu(III) species and the subsequent reductive elimination
via an enyl[s + p]-type transition state.11 Given the selective
formation of Z-olen aminoarylation products, we cannot rule
out the possibility of coordination between the neighboring
sulfonamide and copper.
We examined this efficient protocol for the aminoarylation
of 1,3-butadiene with a series of aryl Grignard reagents (Table
2). The reaction was compatible with a range of para-substituted
phenyl rings (entries 2–4). Meta- and ortho-substitution were
also tolerated (entries 5–8). Polycyclic aromatic hydrocarbons
were efficiently incorporated into the aminoarylation products
(entries 9 and 10). Most notably, a heteroaromatic Grignard
reagent was compatible with the transformation (entry 11).
Interestingly, the scope of the aminoarylation of butadiene was
limited to aryl Grignard reagents. The use of aliphatic Grignard
reagents resulted in a selective aminosulfuration process
(entries 12 and 13). Although we do not currently understand
the origin of this distinct product selectivity for aliphatic
Grignard reagents, the overall transformation represents a
unique difunctionalization of dienes with carbon and sulfur
functional groups.
Results and discussion
The proposed strategy for diene difunctionalization was initially
evaluated for 1,3-butadiene 5 (Table 1). Sparging of sulfurdii-
mide 2 with butadiene for 10 minutes resulted in the efficient
formation of cyclic sulnamide 6. In the absence of a metal
catalyst, cycloadduct 6 did not yield coupled products 7 or 8
when treated with phenylmagnesium bromide (entry 1). Our
previous experience with the copper-catalyzed coupling of
simple allylic sulnamides and Grignard reagents suggested
that copper complexes would be a reasonable starting point for
the selective functionalization of cycloadduct 6, despite the
inherent differences between these two classes of substrates.6
Copper(I) thio-phene-2-carboxylate (CuTc) exhibited a solvent
dependent ability to catalyze the formation of aminoarylation
products 7 and 8 (entries 2–4), with ethereal solvents such as
DME proving to be optimal (entry 2). Despite the usual
g-selectivity of copper-catalyzed allylic alkylation systems,8,9
cycloadduct 6 was transformed with high a-selectivity to
product 7.
Aer an examination of a series of copper sources (entries
5–9), CuBr$SMe2 was selected as the most effective catalyst
(entry 9). Three equivalents of phenylmagnesium bromide were
necessary for the efficient formation of aminoarylation product
7 (entries 10 and 11). Gratifyingly, without isolation of cyclo-
adduct 6, 1,3-butadiene 5 underwent selective difunctionaliza-
tion in a single reaction ask in less than one hour to afford
aminoarylation product 7, which was isolated in 88% yield with
We next explored the aminoarylation of substituted dienes,
with the expectation that the difunctionalization of unsym-
metrical substrates would occur in a regioselective manner
(Table 3). Symmetrical 2,3-disubstitution of the diene did not
affect the efficiency of the reaction (entry 1). Moreover,
Table 1 Optimization of 1,4-aminoarylationa
Entry
CuX (2 mol%)
PhMgBr (equiv.)
Solvent
Temperature (ꢀC)
Time (h)
Yieldb (%)
7 : 8
1
2
3
4
5
6
7
8
—
CuTc
CuTc
CuTc
CuCl
CuBF4
Cu(OTf)2
Cul
CuBr$SMe2
CuBr$SMe2
CuBr$SMe2
CuBr$SMe2
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.0
2.0
3.0
DME
DME
CH2Cl2
PhMe
DME
DME
DME
DME
DME
DME
DME
DME
23
23
23
23
23
23
23
23
2
0.5
2
<5
75
<5
<5
60
67
70
78
—
14 : 1
—
2
—
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
15 : 1
9 : 1
10 : 1
10 : 1
20 : 1
20 : 1
20 : 1
9 : 1
9
23
23
23
95 (82)c
21
10
11
12d
45
ꢁ78 to 23
88c
a
Reaction conditions. Step 1: sulfurdiimide 2 (1 equiv.), solvent (0.2 M), 1,3-butadiene (sparge for 10 min and then stir for 10 min at 23 ꢀC). Step 2:
b
c
CuX (2 mol%), Ph–MgBr (3 equiv.), solvent (0.2 M). Two-step HNMR yield, with 1,4-dimethoxybenzene as an internal standard. Isolated yield.
d
Two steps performed in one ask, without isolation of cycloadduct 6.
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Table 2 Substrate scope of Grignard reagentsa
Table 3 Substrate scope of 1,3-dienesa
Entry R–MgBr
Major product (9)
Yieldb (%) 9 : 10
1
2
88
82
9 : 1
9 : 1
Entry Olen
Product
Yieldb (%) 4 : 11
1
2
61
77
>20 : 1
>20 : 1
3
4
87
89
7 : 1
5 : 1
3
79
>20 : 1
5
6
7
8
66
56
32
95
5 : 1
4
5
80
56
>20 : 1
>20 : 1
10 : 1
>20 : 1
>20 : 1
6
90
85
4 : 1
5 : 1
7
9
81
85
>20 : 1
7 : 1
a
Reaction conditions. Sulfurdiimide 2 (1 equiv.), DME (0.2 M), diene 1
(1.5 equiv.), stir for 10 min at 23 ꢀC; CuBr$SMe2 (2 mol%), R–MgBr (3
equiv.). b Isolated yield.
10
regioisomer when 1-substituted dienes were subjected to the
reaction conditions (entries 4 and 5). Cyclic dienes were also
efficiently functionalized, furnishing a mixture of the a-
substituted and g-substituted aminoarylation products (entries
6 and 7). The anti orientation of the phenyl ring and sulfon-
amide in the cyclic products is consistent with an oxidative
addition of copper to the [4 + 2] cycloadduct with inversion,
followed by reductive elimination with retention.8
To expand the synthetic utility of the 1,4-aminoarylation of
dienes, we examined this method in a more stereochemically
complex setting. We subjected 1,4-disubstituted unsymmetrical
diene 12 to the optimized reaction conditions, which generated
acyclic products with two stereocenters (Scheme 3). To our
11
12
75
55
12 : 1
—
13
45
—
a
Reaction conditions. Sulfurdiimide 2 (1 equiv.), DME (0.2 M), 1,3-
butadiene (sparge for 10 min and then stir for 10 min at 23 ꢀC);
CuBr$SMe2 (2 mol%), R–MgBr (3 equiv.). b Isolated yield.
unsymmetrical 2-substituted dienes were converted to the delight, our method for aminoarylation yielded predominantly
aminoarylation products 4 as single regioisomers with exquisite regioisomer 13 (4.2 : 1 ratio), which was attributed to the subtle
a-selectivity (entries 2 and 3). The regioselectivity of the hetero- inductive differences of the silyl ether and methyl group in the
Diels–Alder reaction can be rationalized by frontier molecular [4 + 2] cycloaddition with sulfurdiimide 2. In addition, both
orbital analysis of the concerted [4 + 2] cycloaddition between regioisomers 13 and 14 were isolated as single diastereomers,
dienes 1 and sulfurdiimide 2.12 This argument for regiose- which was consistent with a diastereoselective [4 + 2] cycload-
lectivity is supported by the selective formation of a single dition followed by a stereospecic copper-catalyzed arylation.13
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regioselective generation of internal olen 4 over terminal
olen 11 for unsymmetrical acyclic dienes (Table 3, entries 2–5).
Conclusions
In summary, we have developed a regioselective and diaster-
eoselective aminoarylation of acyclic and cyclic 1,3-dienes with
a sulfurdiimide reagent and aryl Grignard reagents. The high
selectivity in product formation is a result of regioselective [4 +
2] oxidation of unsymmetrical substrates followed by a-selective
copper-catalyzed allylic alkylation. Overall, this process converts
1,3-dienes into aminoarylation products with three new func-
tional groups (an aryl ring, a sulfonamide, and a Z-olen),
which can be further manipulated to generate complex mole-
cules efficiently from a simple class of starting materials. The
utility of the aminoarylation reaction in complex natural
product synthesis and the development of an enantioselective
aminoarylation process are currently under investigation.
Scheme 3 Regioselective and diastereoselective aminoarylation of
acyclic 1,3-dienes.
We propose the mechanism depicted in Scheme 4 for the
copper-catalyzed allylic substitution step. One equivalent of
Grignard reagent initially reacts with [4 + 2] cycloadduct 3 to
generate activated allylic sulmide 15. The susceptibility of
sulnamide 15 to nucleophilic attack is similar to the proposed
reactivity of allylic sulfoxides in the presence of Grignard
reagents.14 Sulmide 15 and the organocuprate reagent form
p-complex 16. While analogous p-complexes of other allylic
electrophiles undergo facile oxidative addition with mono-
alkylcuprates followed by selective SN20-type displacement with
Grignard reagents to form branched products,8 we surmise that
the unique leaving group in p-complex 16 renders this inter-
mediate stable to oxidative addition. A second equivalent of
Grignard reagent is necessary for the formation of the more
reactive dialkylcuprate 17, which proceeds through an oxidative
addition pathway to p-allylcopper(III) complex 21 and sulmide
leaving group 18. Byproduct 18 is decomposed by a third
equivalent of Grignard reagent,15 which is consistent with the
requirement of 3 equivalents of Grignard reagent in the allylic
functionalization protocol. Dialkyl p-allylcopper(III) complexes
such as 21 (where R1 ¼ H) are known to favor the formation of
a-products over g-products,8,16 which may account for the
Acknowledgements
Financial support was provided by the W. W. Caruth, Jr
Endowed Scholarship, the Robert A. Welch Foundation (Grant I-
1748), the National Institutes of Health (1R01GM102604-01),
the Chilton Foundation Fellowship (H.B.), the University of
Texas System Chemistry and Biology Training Grant (L.B.), and
the Sloan Research Fellowship (U.K.T.). We thank Dr. Vincent
Lynch for X-ray structural analysis.
Notes and references
1 J. E. Baeckvall, Acc. Chem. Res., 1983, 16, 335.
¨
2 For seminal examples, see: (a) B. Akermark, J.-E. Backvall,
¨
A. Lowenborg and K. Zetterberg, J. Organomet. Chem., 1979,
166, C33; (b) P. G. Andersson and J. E. Baeckvall, J. Am.
Chem. Soc., 1992, 114, 8696; (c) H. Du, W. Yuan, B. Zhao
and Y. Shi, J. Am. Chem. Soc., 2007, 129, 11688; (d) L. Xu,
H. Du and Y. Shi, J. Org. Chem., 2007, 72, 7038; (e) B. Zhao,
H. Du, S. Cui and Y. Shi, J. Am. Chem. Soc., 2010, 132,
3523; (f) B. Zhao, X. Peng, Y. Zhu, T. A. Ramirez,
R. G. Cornwall and Y. Shi, J. Am. Chem. Soc., 2011, 133,
20890; (g) C. S. Jeffrey, D. Anumandla and C. R. Carson,
˜
Org. Lett., 2012, 14, 5764; (h) A. Lishchynskyi and K. Muniz,
Chem.–Eur. J., 2012, 18, 2212; (i) R. G. Cornwall, B. Zhao
and Y. Shi, Org. Lett., 2013, 15, 796.
3 For a recent example, see: R. W. Coscia and T. H. Lambert, J.
Am. Chem. Soc., 2009, 131, 2496.
4 (a) R. C. Larock, N. Berrios-Pena and K. Narayanan, J. Org.
Chem., 1990, 55, 3447; (b) D. Xing and D. Yang, Org. Lett.,
2013, 15, 4370; (c) F. G. Stakem and R. F. Heck, J. Org.
Chem., 1980, 45, 3584.
5 S. M. Weinreb, Acc. Chem. Res., 1988, 21, 313.
6 (a) H. Bao and U. K. Tambar, J. Am. Chem. Soc., 2012, 134,
18495; (b) H. Bao, L. Bayeh and U. K. Tambar, Angew.
Chem., Int. Ed., 2014, 53, 1664.
7 For early examples of transition metal catalyzed alkylations
with sulfur leaving groups, see: (a) V. Calo, L. Lopez and
Scheme 4 Mechanism of copper-catalyzed allylic substitution step.
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W. F. Carlucci, J. Chem. Soc., Perkin Trans. 1, 1983, 2953; (b)
V. Calo, L. Lopez and G. Pesce, J. Chem. Soc., Chem.
and S. Murahashi, J. Am. Chem. Soc., 1977, 99, 2361; (c)
H. L. Goering, E. P. Seitz and C. C. Tseng, J. Org. Chem.,
1981, 46, 5304.
`
Commun., 1986, 1252; (c) V. Calo, L. Lopez and G. Pesce, J.
Organomet. Chem., 1988, 353, 405; (d) H. Okamura and 11 (a) M. Yamanaka, S. Kato and E. Nakamura, J. Am. Chem.
H. Takei, Tetrahedron Lett., 1979, 20, 3425.
Soc., 2004, 126, 6287; (b) E. R. Bartholomew, S. H. Bertz,
S. Cope, M. Murphy and C. A. Ogle, J. Am. Chem. Soc.,
2008, 130, 11244; (c) N. Yoshikai, S.-L. Zhang and
E. Nakamura, J. Am. Chem. Soc., 2008, 130, 12862.
¨
`
8 (a) A. Alexakis, J. E. Backvall, N. Krause, O. Pamies and
´
M. Dieguez, Chem. Rev., 2008, 108, 2796; (b) C. A. Falciola
and A. Alexakis, Eur. J. Org. Chem., 2008, 3765; (c)
S. R. Harutyunyan, T. den Hartog, K. Geurts, 12 I. Fleming, Frontier Orbitals and Organic Chemical Reactions,
A. J. Minnaard and B. L. Feringa, Chem. Rev., 2008, 108, Wiley, Chicester, U.K., 2000.
2824; (d) N. Yoshikai and E. Nakamura, Chem. Rev., 2011, 13 The relative stereochemistry of the products 13 and 14 was
112, 2339.
inferred based on the anti stereochemistry of the products
obtained from the aminoarylation of cyclic dienes (Table 3,
entries 6–7).
9 For other examples of a-selectivity in Grignard cross-
coupling reactions of allylic electrophiles with some sulfur-
based leaving groups, see: (a) A. M. Lauer, F. Mahmud and 14 (a) Y. Gendreau, J. F. Normant and J. Villieras, J. Organomet.
J. Wu, J. Am. Chem. Soc., 2011, 133, 9119; (b) X. Han,
Y. Zhang and J. Wu, J. Am. Chem. Soc., 2010, 132, 4104. For
computational studies of a-selectivity with some sulfur-
based leaving groups, see: (c) W. Sheng, M. Wang, M. Lein,
L. Jiang, W. Wei and J. Wang, Chem.–Eur. J., 2013, 19, 14126.
Chem., 1977, 142, 1; (b) M. Julia, A. Righini and
J.-N. Verpeaux, Tetrahedron Lett., 1979, 20, 2393; (c)
Y. Masaki, K. Sakuma and K. Kaji, J. Chem. Soc., Chem.
Commun., 1980, 434; (d) G. Deleris, J. Dunogues and
A. Gadras, Tetrahedron Lett., 1984, 25, 2135.
10 For early reports of preserving olen geometry in copper- 15 D. N. Harpp, S. M. Vines, J. P. Montillier and T. H. Chan, J.
mediated allylic alkylations, see: (a) J. Levisalles, Org. Chem., 1976, 41, 3987.
M. Rudler-Chauvin and H. Rudler, J. Organomet. Chem., 16 N. Yoshikai and E. Nakamura, Chem. Rev., 2011, 112,
1977, 136, 103; (b) Y. Tanigawa, H. Kanamaru, A. Sonoda
2339.
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