Functionalized chromans and isochromans via a diastereoselective Pd(0)-catalyzed carboiodination

Article abstract of DOI:10.1021/ol302111y

A diastereoselective approach to isochromans and chromans via Pd(0)-catalyzed carboiodination is reported. The transformations using thismethodology display excellent yields and diastereoselectivities as well as broad functional group compatibility. The selectivity observed in these cyclizations, forming isochroman or chroman targets, is postulated to originate from the minimization of A^1,2 strain and axial-axial interactions, respectively. This method has also been used to highlight the concept of reversible oxidative addition to carbon-iodine bonds in polyiodinated substrates.

Full text of DOI:10.1021/ol302111y

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4806–4809
Functionalized Chromans and
Isochromans via a Diastereoselective
Pd(0)-Catalyzed Carboiodination
David A. Petrone, Hasnain A. Malik, Antonin Clemenceau, and Mark Lautens*
Department of Chemistry, Davenport Chemical Laboratories, 80 St. George Street,
University of Toronto, Toronto, Ontario M5S 3H6, Canada
mlautens@chem.utoronto.ca
Received July 31, 2012
ABSTRACT
A diastereoselective approach to isochromans and chromans via Pd(0)-catalyzed carboiodination is reported. The transformations using this methodology
display excellent yields and diastereoselectivities as well as broad functional group compatibility. The selectivity observed in these cyclizations, forming
isochroman or chroman targets, is postulated to originate from the minimization of A1,2 strain and axialÀaxial interactions, respectively. This method has
also been used to highlight the concept of reversible oxidative addition to carbonÀiodine bonds in polyiodinated substrates.
Heterocycles appear in numerous bioactive compounds
and important synthetic intermediates.1 The continued
development of efficient strategies which allow the synthe-
sis of these heterocyclic frameworks is of great importance
to the synthetic community.2 Transition-metal catalyzed
methods resulting in newly formed carbonÀcarbon bonds
have emerged as an effective strategy toward this
end.3 Furthermore, there is a continuing need for the
development of atom-economical variants of organometallic
transformations that result in the retention of important
functionality within a molecule. Our group4aÀc and others4d,e
are interested in using Pd(0)-catalyzed carbohalogenation5
as an efficient and atom-economical6 synthetic strategy
toward complex ring systems. Recently, we reported a
Pd(0)-catalyzed bromide to iodide exchange reaction which
was incorporated within various domino cyclizations.7 These
(4) (a) Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2010, 132,
11416–11417. (b) Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2011,
133, 1778–1780. (c) Lan, Y.; Liu, P.; Newman, S. G.; Lautens, M.; Houk,
K. N. Chem. Sci. 2012, 3, 1987–1995. (d) Liu, H.; Li, C.; Qiu, D.; Tong,
X. J. Am. Chem. Soc. 2011, 133, 6187–6193. (e) Liu, H.; Chen, C.; Wang,
L.; Tong, X. Org. Lett. 2011, 13, 5072–5075.
(5) For the seminal report of CÀI reductive elimination using rho-
dium, see: Feller, M.; Iron, M. A.; Shimon, L. J. W.; Diskin-Posner, Y.;
Leitus, G.; Milstein, D. J. Am. Chem. Soc. 2008, 130, 14374–14375.
(6) (a) Trost, B. M. Science 1991, 254, 1471–1477. (b) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259–281.
(1) (a) Majumdar, K. C.; Chattopadhyay, S. K. Heterocycles in
Natural Product Synthesis; VCH: New York, 2011.
(2) Bolm, C.; Beller, M. Transition Metals for Organic Synthesis;
VCH: New York, 2004; Vols. 1 and 2.
(3) (a) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285–2309. (b)
Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644–4680. (c) Li, J. J.;
Gribble, G. W. Palladium in Heterocyclic Chemistry; Pergamon:
New York, 2000. (d) Negishi, E. Handbook of Organopalladium Chemistry
for Organic Synthesis; Wiley and Sons: New York, 2002; Vols. 1 and 2. (e)
Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169–196.
(7) Newman, S. G.; Howell, J. K.; Nicolaus, N.; Lautens, M. J. Am.
Chem. Soc. 2011, 133, 14916–14919.
r
10.1021/ol302111y
Published on Web 09/06/2012
2012 American Chemical Society

reactions afforded a diverse set of complex polycyclic pro-
ducts in good yields with moderate to excellent levels of
diastereocontrol. We were interested in exploring levels of
diastereocontrol in this reaction for the synthesis of chroman
and isochroman motifs, as their derivatives display interest-
ing biological and medicinal activity.8
Table 1. Reaction Optimization
Recent synthetic strategies toward their synthesis include
the use of Lewis acids,9 organocatalysis,10 and palladium
catalysis,11 among others.12 Despite these methods affording
noteworthy reactivity and stereoselectivity, there is a lack of
general and unified approaches toward both these hetero-
cyclic skeletons.13 We envisioned utilizing our palladium
catalyzed carboiodination reaction as an integrated approach
to access both of these molecular frameworks. Herein, we
report the synthesis of various functionalized chromans and
isochromans via a highly diastereoselective intramolecular
Pd(0)-catalyzed carboiodination of alkenyl aryl iodides.
Our investigation began by analyzing the effectiveness of
various bulky phosphine-containing Pd(0) precatalysts on
the intramolecular cyclization of 1a (Table 1). In accor-
dance with previous reports,6b,7 both Pd[(PCy3)]2 (entry 1)
and Pd[P(o-tol)3]2 (entry 2) gave no desired isochroman
product. The more bulky ligand14 PtBu2Ph only afforded
trace conversion to the desired product 2a (entry 3) de-
spite performing moderately well in previous systems.
Q-Phos was much better, affording 62% of the desired
product with a diastereomeric ratio of 90:10 (entry 4).
mol %
yield
dr
L
PdL2
(%)a,b
(cis/trans)c
P(o-tol)3
PCy3
5.0
5.0
5.0
5.0
5.0
5.0
2.5
0
À
0
À
PtBu2Ph
QPhos
PtBu3
<5
À
62
90:10
94:6
94:6
91:9
94d
47(53)
77(23)
PtBu3
PtBu3
e
a Calculated by 1H NMR analysis of the crude reaction mixture using
1,3,5-trimethoxybenzene as an internal standard. b Value in brackets
represents yield of unreacted starting material. c Calculated by 1H NMR
analysis of the crude reaction mixture. d Isolated yield. e Reaction run in
the absence of NEt3.
Table 2. Scope of Isochroman Synthesisa
When 5 mol % PtBu3 was employed, both yield and
15
diastereoselectivity increased to94% and 94:6, respectively
(entry 5). In the absence of NEt3 we noticed a significant
decrease in yield (47%) but no decrease in stereoselectivity
(entry 6). Decreasing the catalyst loading to 2.5 mol %
caused a marked decrease in overall yield (77%, entry 7).
The optimal reaction conditions were found to be 5.0 mol %
Pd[(PtBu3)]2, 1 equiv of NEt3 in toluene at 110 °C. The
requirement of an amine base is postulated to assist the
regeneration of Pd(0) from Pd(II)HX, which may result
from trace intermolecular Mizoroki-Heck type processes.
(8) Ellis, G. P.; Lockhart, I. M. The Chemistry of Heterocyclic
Compounds, Chromenes, Chromanones, and Chromones; VCH: New York,
2007.
(9) van Lingen, H. L.; Zhuang, W.; Hansen, T.; Rutjes, F. P. J. T.;
Jorgensen, K. A. Org. Biomol. Chem. 2003, 1, 1953–1958.
(10) (a) Lee, Y.; Seo, S. W.; Kim, S. G. Adv. Synth. Catal. 2011, 353,
2671–2675. (b) Yu, D. F.; Wang, Y.; Xu, P. F. Adv. Synth. Catal. 2011,
353, 2960–2965. (c) Enders, D.; Urbanietz, G.; Hahn, R.; Raabe, G.
Synthesis 2012, 44, 773. (d) Hu, F.; Guan, X.; Shi, M. Tetrahedron 2012,
68, 4782–4790.
(11) (a) Yu, L.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem.
Soc. 2010, 132, 5916–5921. (b) Leibeling, M.; Milde, B.; Kratzert, D.;
Stalke, D.; Werz, D. B. Chem.;Eur. J. 2011, 17, 9888–9892. (c) Ward,
A. F.; Xu, Y.; Wolfe, J. P. Chem. Commun. 2012, 48, 609–611. (d)
Cannon, J. S.; Olsen, A. C.; Overman, L. E.; Solomon, N. S. J. Org.
Chem. 2012, 77, 1961–1973.
(12) (a) Medeiros, M. R.; Narayan, R. S.; McDougal, N. T.; Schaus,
S. E.; Porco, J. A., Jr. Org. Lett. 2010, 12, 3222–3225. (b) Kern, N.;
Blanc, A.; Weibel, J. M.; Pale, P. Chem. Commun. 2011, 47, 6665–6667.
(c) Shen, H. C. Tetrahedron 2009, 65, 3931–3952.
a Reaction conditions: Aryl iodide (0.2 mmol, 0.05 M), NEt3
(0.2 mmol) Pd(PtBu3)2 (5 mol %), toluene. b Isolated yield. c dr calculated
by 1H NMR analysis of the crude reaction mixtures. d Reaction run at
0.1 M with respect to the aryl iodide. e Yield obtained when 100 mol % of
pyridine was added to the reaction mixture. f 1.0 equiv of iPr2NEt was
used instead of NEt3.
(13) Leibeling, M.; Koester, D. C.; Pawliczek, M.; Schild, S. V.;
Werz, D. B. Nat. Chem. Biol. 2010, 6, 2010.
(14) Tolman, C. A. Chem. Rev. 1977, 77, 313–348.
(15) For syntheis of this ligand, see: (a) Li, H.; Grasa, G. A.; Colacot,
T. J. Org. Lett. 2010, 11, 3332–3335. (b) Colacot, T. J.; Grasa, G. A.; Li
H. B. (Johnson Matthey Public Ltd. Co., USA) Preparation of a metal
complex. International Patent WO 2010/128316 A1, November 11, 2010.
A diverse set of substituted alkenyl aryl iodides were
subjected to the reaction conditions to test the scope and
selectivity of this transformation (Table 2). When the
cyclization of 1a was conducted on a 2 mmol scale, the
Org. Lett., Vol. 14, No. 18, 2012
4807

Table 3. Scope of Chroman Synthesisa
Scheme 1. Stereochemical Models Describing the
Diastereoselective Carbopalladation Step for
(a) Isochroman and (b) Chroman Formation
a Reaction conditions: Aryl iodide (0.2 mmol, 0.1 M), NEt3 (0.2 mmol),
Pd(PtBu3)2 (5 mol %), toluene. b Isolated yield. c Calculated by 1H NMR
analysis of the crude reaction mixtures.
81% yield and 91:9 diastereoselectivity, while cyclopropyl
2h and n-propyl-containing 2i analogs were obtained with
yields of 93% and 86% and diastereoselectivities of 90:10
and 89:11, respectively. This general trend of stereoselec-
tivity is dependent on overall steric factors in order to
obtain high levels of diastereoselectivity. As evidence of
these steric requirements, o-CF3 functionalized 2j was
obtained in 88% yield as a single observable diastereomer.
It is noteworthy that an enantiomerically enriched precursor
(S)-1k was prepared and cyclized to the corresponding
isochroman (3R,4R)-2k with high levels of diastereoselec-
tivity and no apparent erosion of enantiomeric excess (eq 1).
Figure 1. X-ray structures of 2b and 4c.
corresponding isochroman was afforded in 88% yield with
no erosion of diastereoselectivity. Benzodioxole substituted
2b was afforded in 91% yield with 96:4 diastereoselectivity.
The cis isomer was unambiguously identified as the major
product by X-ray crystallographic analysis (Figure 1a). This
stereoselectivity of isochroman formation is thought to arise
from the decreased A1,2 strain16 of the tether substituent and
the vinylic CH3 prior to carbopalladation (Scheme 1a).
Heterocyclic substituents were tolerated affording the
desired isochromans 2c and 2d in 85% and 94% yields with
92:8 and 91:9 diastereoselectivity, respectively. 3-Pyridyl
substituted 2f was obtained in 35% yield with 98:2 diaste-
reoselectivity. However, the 2-pyridyl analog did not under-
go the desired transformation, providing only recovered
starting material. Cyclohexyl containing 2g was isolated in
This methodology was further applied to the synthesis
of substituted chromans (Table 3). 2-Phenyl chroman 4a
was obtained in 81% yield and 93:7 diastereoselectivity
(entry 1). A 1-napthalene analog 4b was afforded in
96% yield as a single diastereomer (entry 2). Notably, a
switch in stereochemistry occurs from cis to trans with respect
(16) (a) Hoffman, R. W. Chem. Rev. 1989, 89, 1841–1860. (b)
JohnsonF. Chem. Rev. 1968, 68, 375–413.
4808
Org. Lett., Vol. 14, No. 18, 2012

to the isochroman variants, and this stereochemical outcome
was unambiguously determined through X-ray analysis
(Figure 1b). The observed stereoselectivity is thought to
originate from the minimization of axialÀaxial interactions
in the carbopalladation step (Scheme 1). This reaction is ex-
ceptionally tolerant toward heteroatoms, halogens, and elec-
tron-withdrawing groups, as the desired chromans were ob-
tained with excellent yields and diastereoselectivities (4cÀe).
Remarkably, di-iodinated substrate 3f was converted to
the corresponding chroman 4f in 70% yield and 91:9
diastereoselectivity without deleterious byproduct forma-
tion (eq 2). This result is consistent with an earlier report
that highlights the possibility of reversible oxidative addi-
tion to CÀI bonds by the Pd-catalyst, since it might be
anticipated that the 4-iodo would react before the more
hindered 2-iodo group.4a
yields and high diastereoselectivities and have broad func-
tional group compatibility. The stereochemistry observed
in these cyclizations is postulated to originate from the
minimization of A1,2 strain and axialÀaxial interactions. A
stereochemical model has been presented. Studies to
further understand the involvement of an amine base, as
well as computational analyses to explore the energetics of
these cyclizations, are currently underway in our laboratory
and will be reported in due course.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (NSERC) and
the University of Toronto for financial support. NSERC/
Merck-Frosst Canada is thanked for an Industrial Research
Chair. D.A.P. thanks NSERC for a postgraduate scholar-
ship (CGS-M). We thank Johnson Matthey Catalysis and
Chiral Technologies for donating palladium catalysts, in-
cluding Pd(PtBu3)2, and Alan J. Lough (Chemistry Depart-
ment, University of Toronto) for obtaining the crystal
structures of 2b and 4c. David A. Candito (University of
Toronto) is thanked for helpful discussions.
Supporting Information Available. Experimental pro-
cedures, spectral data for all new compounds, and crystal-
lographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed a common approach
for the diastereoselective synthesis of isochroman and
chroman frameworks via a Pd(0)-catalyzed carboiodination.
These transformations display generally good to excellent
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
4809