Diastereomeric reissert compounds of isoquinoline and 6,7-dimethoxy-3,4- dihydroisoquinoline in stereoselective synthesis

Article abstract of DOI:10.1021/jo070786k

(Chemical Equation Presented) Chiral acid chlorides were reacted with isoquinoline and 6,7-dimethoxy-3,4-dihydroisoquinoline to form diastereomeric Reissert compounds 8-11 and 18-21, respectively. The best diastereoselectivity (80:20) was achieved in formation of the 9-phenylmenthyl derivative 20. The diastereomers of 2-l-menthoxy-carbonyl-1,2-dihydroisoquinaldonitriles (S)-8/(R)-8), formed in equal amounts, were inseparable. However, the individual diastereomers of 2-cholesteryloxycarbonyl-1,2-dihydroisoquinaldonitriles ((R)-11 and (5)-11) and the 2-l-menthoxycarbonyl-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinaldonitriles ((S)-19/(R)-19)) were each readily purified. (S)-8/(R)-8 (1:1) via the corresponding anions (NaH, -40°C, DMF) with pivaldehyde yielded in 82:18 predominance the S-diastereomer of 1-isoquinolyl tert-butyl carbinyl l-menthyl carbonate ((S)-12), which was obtained in pure form by a single recrystallization; hydrolysis produced 99% pure S-(-)-1-isoquinolyl tert-butyl carbinol [(S)-16]. Reactions of the anions of diastereomeric Reissert compounds, either as mixtures or pure single species, with aromatic aldehydes and alkyl halides proceeded with at best modest selectivity (diastereomeric ratios up to 66:34 and 72:28, respectively). Therefore, it is concluded that the Reissert anions are either planar or rapidly inverting tetrahedral structures.

Full text of DOI:10.1021/jo070786k

Diastereomeric Reissert Compounds of Isoquinoline and
6,7-Dimethoxy-3,4-dihydroisoquinoline in Stereoselective Synthesis|
Harry W. Gibson,* Michael A. G. Berg, Jennifer Clifton Dickson,† Pierre R. Lecavalier,‡
Hong Wang,§ and Joseph S. Merola
Department of Chemistry, Virginia Polytechnic Institute and State UniVersity, Blacksburg, Virginia 24061
hwgibson@Vt.edu
ReceiVed April 15, 2007
Chiral acid chlorides were reacted with isoquinoline and 6,7-dimethoxy-3,4-dihydroisoquinoline to form
diastereomeric Reissert compounds 8-11 and 18-21, respectively. The best diastereoselectivity (80:20)
was achieved in formation of the 9-phenylmenthyl derivative 20. The diastereomers of 2-l-menthoxy-
carbonyl-1,2-dihydroisoquinaldonitriles (S)-8/(R)-8), formed in equal amounts, were inseparable. However,
the individual diastereomers of 2-cholesteryloxycarbonyl-1,2-dihydroisoquinaldonitriles ((R)-11 and (S)-
11) and the 2-l-menthoxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinaldonitriles ((S)-19/(R)-19))
were each readily purified. (S)-8/(R)-8 (1:1) via the corresponding anions (NaH, -40 °C, DMF) with
pivaldehyde yielded in 82:18 predominance the S-diastereomer of 1-isoquinolyl tert-butyl carbinyl
l-menthyl carbonate ((S)-12), which was obtained in pure form by a single recrystallization; hydrolysis
produced 99% pure S-(-)-1-isoquinolyl tert-butyl carbinol [(S)-16]. Reactions of the anions of
diastereomeric Reissert compounds, either as mixtures or pure single species, with aromatic aldehydes
and alkyl halides proceeded with at best modest selectivity (diastereomeric ratios up to 66:34 and 72:28,
respectively). Therefore, it is concluded that the Reissert anions are either planar or rapidly inverting
tetrahedral structures.
SCHEME 1. Syntheses of “Normal” Isoquinoline Reissert
Compounds 1 and Urethane Isoquinoline Reissert
Compounds 2 from Isoquinoline (a) and
3,4-Dihydroisoquinoline (b)
Introduction
Reissert compounds are R-(acylamino)nitriles formed by the
formal addition of acyl nitriles to imine bonds.1 Isoquinoline
Reissert compounds, 2-acyl-1-cyano-1,2-dihydroisoquinolines
of general structure 1a (Scheme 1), for example, are prepared
by reaction of isoquinoline and acid chlorides in the presence
of a cyanide ion source.2-4 3,4-Dihydroisoquinolines are
converted to analogous compounds 1b.5 Aromatic and aliphatic
| This article is dedicated to the memory of the late Prof. Frank D. Popp.
† Current address: Wikoff Color Corp., 803 Phillips Street, Shelby, NC 28150
‡ Current address: Defence R&D Canada Suffield, Medicine Hat, AB, Canada
T1A 8K6
acid chlorides and a variety of heterocycles may be employed
to make Reissert compounds.1,6 Chloroformates produce the
corresponding urethane Reissert compounds, for example, 2a
and 2b (Scheme 1).1
§ Current address: Alkermes, Inc., Cambridge, MA 02139
(1) (a) Popp, F. D. In Quinolines; Jones, G., Ed.; Wiley and Sons: New
York, 1982; pp 353-375. (b) Popp, F. D. AdV. Heterocycl. Chem. 1968, 9,
1-25. Popp, F. D. AdV. Heterocycl. Chem. 1979, 24, 187-214. (c) McEwen,
W. E.; Cobb, R. L. Chem. ReV. 1955, 55, 511-549. (d) Cooney, J. V.
Heterocycl. Chem. 1983, 20, 823-837.
(4) (a) Ruchirawat, S.; Phadungkul, N.; Chuankamnerdkarn, M.; Thebt-
aranonth, C. Heterocycles 1977, 6, 43-46. (b) Bhattacharjee, D.; Popp, F.
D. J. Heterocycl. Chem. 1980, 17, 1211-1212.
(5) (a) Elliot, I. W.; Leflore, J. O. J. Org. Chem. 1963, 28, 3181-3184.
(b) Gibson, H. W.; Popp, F. D. J. Chem. Soc. C 1966, 1860-1864. (c)
Shamma, M.; Jones, C. D. J. Org. Chem. 1970, 35, 3119-3121. (d)
Rozwadowska, M. D.; Bro´zda, D. Bull. Acad. Pol. Sci., Ser. Sci. Chim.
1978, 26, 33-38. (e) Jackson, Y. A.; Stephenson, E. K.; Cava, M. P.
Heterocycles 1993, 36, 1047-1050.
(2) Reissert, A. Chem. Ber. 1905, 38, 1603.
(3) (a) Popp, F. D.; Blount, W. Chem. Ind. 1961, 550. (b) Popp, F. D.;
Blount, W.; Melvin, P. J. Org. Chem. 1961, 26, 4930-4932. (c) Popp, F.
D.; Blount, W. J. Org. Chem. 1962, 27, 297-298. (d) Popp, F. D.; Soto,
A. J. Chem. Soc. 1963, 1760-1763.
10.1021/jo070786k CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/26/2007
J. Org. Chem. 2007, 72, 5759-5770
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Gibson et al.
SCHEME 2. Condensation of Isoquinoline Reissert Compound 1a with Aldehydes To Form 1-Isoquinoloyl Carbinyl Esters
SCHEME 3. Condensation of Isoquinoline Urethane Reissert Compounds with Aldehydes To Form Cyclic Urethanes or
1-Isoquinoloyl Carbinyl Carbonates
SCHEME 4 Reactions of Isoquinoline Reissert Compounds 1 and 2 with Primary and Secondary Alkyl Halides, Leading to
Derivatives 6 and 7
The proton R to the cyano group of Reissert compounds, for
example, H1 of 1 or 2 is acidic and may be abstracted by a
variety of bases, and the resultant anions are excellent nucleo-
philes that undergo a number of reactions with proven utility
in elaboration of nitrogen heterocycles.1 When an isoquinoline
Reissert anion from 1a is treated with an aldehyde, the ester 3
of a 1-(R-hydroxyalkyl)isoquinoline forms via the intermediates
shown in Scheme 2. “Dhihydro-Reissert compounds” 1b do not
undergo this reaction because of the lack of rearomatization as
a driving force.
When urethane Reissert compounds 2a are treated similarly,
an alternate pathway is available, namely, elimination of
alkoxide from the cyclic intermediate, resulting in formation
of the cyclic urethane 4 (Scheme 3). This process can be
circumvented by carrying out the reaction at low-temperature
(<0 °C); under these conditions the carbonate 5 is essentially
the only product.7 Note that in 3, 4, and 5 a new stereocenter is
produced. Again, dihydro-Reissert compounds 2b do not
undergo these processes.
late 1980s. The formation of Reissert compounds proceeds
through an N-acylium intermediate, which undergoes nucleo-
philic addition of the cyanide ion. Thus, Reissert compounds
could conceivably be prepared diastereoselectively if a chiral
acyl portion properly influenced the addition of cyanide ion;
indeed, preliminary molecular mechanics calculations indicated
that this would be the case for some auxiliaries. Also it was
our hope that the resulting chiral Reissert compounds could be
alkylated with high stereoselectivity, providing a convenient
stereoselective route to a number of isoquinoline alkaloids, an
ongoing challenge.10 Preliminary molecular mechanics calcula-
tions indicated that this was a real possibility. Therefore, at that
time we investigated the use of chiral auxiliaries in the form of
the N-acyl moiety of isoquinoline Reissert compounds to provide
diastereoselective reactions of the corresponding anions.11
Recently, the stereoselective synthesis of Reissert compounds
using chiral catalysts has been reported and applied.12 Prompted
by this and other recent reports of use of Reissert compounds
in stereoselective synthesis,13,14 here we report our early work
on the preparation and use of chiral Reissert compounds derived
Reissert compound anions also react with alkyl halides as
shown in Scheme 4.
In spite of the proven utility of Reissert compounds in
syntheses of racemic isoquinoline alkaloids,8,9 there had been
no reports of their utilization in stereoselective synthesis in the
(9) Blasko, G.; Kerkes, P.; Makleit, S. In The Alkaloids: Chemistry and
Pharmacology; Brossi, A., Ed.; Academic Press: New York, 1987; Vol.
21, pp 1-28.
(10) Chrzanowska, M.; Rozwadowska, M. D. Chem. ReV. 2004, 104,
3341-3370.
(6) (a) Jois, Y. H. R.; Gibson, H. W. J. Org. Chem. 1991, 56, 865-867.
(b) Jois, Y. H. R.; Berg, M. A. G.; Merola, J. S.; Gibson, H. W. Tetrahedron
Lett. 1991, 32, 2997-3000. (c) Pandya, A.; Gibson, H. W. J. Org. Chem.
1993, 58, 2851-2855. (d) Jois, Y.; Gibson, H. W. Macromolecules 1994,
27, 2912-2916.
(7) (a) Roswadowska, M. D. Can. J. Chem. 1977, 55, 164-170.
Rozwadowska, M. D.; Bro´zda, D. Tetrahedron Lett. 1978, 589-592. (b)
Rozwadowska, M. D.; Bro´zda, D. Can. J. Chem. 1980, 58, 1239-1242.
(8) Popp, F. D. Heterocycles 1973, 1, 165-180. Popp, F. D. Heterocycles
1980, 14, 1033-1043.
(11) (a) Clifton, J. Studies in Stereoselective Synthesis via Reissert
Compound Chemistry. M.S. Thesis, Virginia Polytechnic Institute and State
University, 1991. (b) Berg, M. A. G. Studies in Stereoselective Synthesis
of 1,2,3,4-Tetrahydroisoquinolines. Ph.D. Dissertation, Virginia Polytechnic
Institute and State University, 1992.
(12) (a) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2000, 122, 6327-6328. (b) Funabashi, K.; Ratni, H.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 10784-10785.
(13) Sieck, O.; Schaller, S.; Grimme, S.; Liebscher, J. Synlett 2003, 3,
337-340.
5760 J. Org. Chem., Vol. 72, No. 15, 2007

Reissert Compounds Bearing Chiral Substituents
SCHEME 5. Synthesis of Chiral Isoquinoline Reissert Compounds
from commercially available, cheap, chiral auxiliaries, and the
condensation reactions of Schemes 2, 3, and 4.
case both urethane isomers were present. In Figure 1c there are
three signals for H1 at 6.43 (a larger peak, presumably two
superimposed signals), 6.25, and 6.20 ppm. The assignment of
the H1 signals was verified by deuteration (see Supporting
Information, Figure S14). H3 appears as a nearly equal pair of
doublets at 6.90 ppm and another nearly equal pair of doublets
at 7.05 ppm (J1,3 ) 1, J3,4 ) 8 Hz). The signal for H4 consists
of seven peaks at 6.05-6.10 ppm (J3,4 ) 8 Hz); two peaks are
Results and Discussion
A. Synthesis of Diastereomeric Reissert Compounds from
Isoquinoline. With chiral acid chlorides and chloroformates,
either commercially available or easily derived from commercial
materials, and isoquinoline (Scheme 5) we prepared the Reissert
compounds summarized in Table 1.
TABLE 1. Synthesis of Diastereomeric Reissert Compounds
1. 2-(Menthoxycarbonyl)-1-,2-dihydroisoquinaldonitriles
(8). It was originally believed that the l-menthyl chloroformate
Reissert compd
yield (%)
diastereomeri ratio
8
9
10
11
96
98
67
91
37
54
50:50a
50:50a
47:53b
41:59c
100:0
100:0
Reissert compound was a single diastereomer because both the
25
melting point (96-97 °C) and the optical rotation ([R]D
)
-63.4, CH2Cl2) were constant upon repeated recrystallization,
and high performance liquid chromatography (HPLC) on Pirkle
covalent phenylglycine and Chiralcel OD columns afforded only
one peak. The [R]D25 value is very close to that recently reported
(-59.6°) for what is claimed to be 8 of >95% diastereomeric
purity.13
(S)-11d
(R)-11d
a Determined by integrations of H1, H3, and H4 signals in the 1H proton
NMR spectra as discussed in the text. b Determined by integration of
C(dO)CH2O signals in the 1H proton NMR spectrum; in one diastereomer
the signal is an AB quartet and in the other it is a singlet. The identities of
the diastereomers are not known. c Determined by HPLC with a Pirkle
phenylglycine column (99:1 hexane/isopropanol, 1 mL/min); listed in order
of elution (see Supporting Information, Figure S2). d The diastereomers of
11 were easily separated morphologically; the identity of the minor S-isomer
was established by X-ray crystallography (see Supporting Information,
Figure S3).
However, examination of the ambient-temperature 270 (or
400) MHz 1H NMR spectrum in CDCl3 (Figure 1a,b) indicated
that signals for H3 were comprised of two broad peaks at 6.87
and 7.01 in a ratio of 39:61, respectively. H4 appeared as a
multiplet at 6.0 ppm and H1 was represented by three distinct
signals at 6.18, 6.22, and 6.38 ppm in a ratio of 62:19:19,
respectively, clearly indicative of a mixture of both diastereo-
mers and urethane isomers (rotamers about the N-CO bond
with its partial double bond character). For comparison, in the
analogous urethane Reissert compound 2a, R ) C2H5,15 H1,
H3, and H4 were observed as simple signals at 6.43 (d, J ∼ 1
Hz), 7.03 (dd, J ∼ 1,8 Hz), and 6.07 (d, J ∼ 8 Hz) ppm at
ambient temperature, respectively. The four possible isomers
of chiral Reissert compounds 8-11 are shown in Scheme 6;
here E and Z refer to the relative positions of the carbonyl
oxygen atom and the cyano group.
Low-temperature (253 K) proton NMR spectroscopy in
CDCl3 demonstrated that both diastereomers of 8 and in each
(14) (a) Reimann, E.; Erdle, W.; Weigl, C.; Polborn, K. Monatsh. Chem.
1999, 130, 313-326. (b) Reimann, E.; Grasberger, F.; Polborn, K. Monatsh.
Chem. 2000, 131, 73-84. (c) Reimann, E.; Grasberger, F.; Polborn, K.
Monatsh. Chem. 2000, 134, 991-1014. (d) Evain, M.; Pauvert, M.; Collet,
S.; Guingant, A. Acta Crystallogr., Sect. E 2002, E58, o1121-o1122. (e)
Pauvert, M.; Collet, S. C.; Bertrand, M.-J.; Guingant, A. Y.; Evain, M.
Tetrahedron Lett. 2005, 46, 2983-2987. (f) Bro´zda, D.; Hoffman, K.;
Rozwadowska, M. D. Heterocycles 2006, 67, 119-122. (g) Kanemitsu,
T.; Yamashita, Y.; Nagata, K.; Itoh, T. Synlett 2006, 1595-1597. (h)
Reimann, E.; Renz, M. Monatsh. Chem. 2007, 138, 211-218.
(15) Popp, F. D.; Katz, L. E.; Klinowski, C. W.; Wefer, J. M. J. Org.
Chem. 1968, 33, 4447-50.
FIGURE 1. 270 MHz 1H NMR spectra of 2-l-menthoxycarbonyl-1,2-
dihydroisoquinaldonitrile [1:1 (S)-8/(R)-8] in CDCl3: (a) bottom, at
25 °C; (b) middle, expanded region 5.9-7.2 ppm at 25 °C; (c) top,
expanded region from 6.0 to 7.2 at -20 °C. The peak at ca. 7.27 ppm
in (a) is due to CHCl3.
J. Org. Chem, Vol. 72, No. 15, 2007 5761

Gibson et al.
SCHEME 6. Four Stereoisomers of Chiral Reissert Compounds 8-11
apparently overlapping. The integrations of the H3 signals
(corroborated by the H1 signals) indicate that the four isomers
have relative populations of 20, 20, 30, and 30%. Changes in
temperature from -45 to +25 °C did not reveal significant
changes in these proportions.
rotations. By careful use of flash chromatography, the NMR
spectra (see Supporting Information, Figure S1) exhibited
changes consistent with these conclusions.
From d-menthyl chloroformate and isoquinoline in the
presence of trimethylsilyl cyanide (TMSCN) was produced 2-d-
menthoxycarbonyl-1,2-dihydroisoquinaldonitrile (9). The dia-
stereomeric mixture of Reissert compounds 9 had an NMR
spectrum identical to that of 8 and an optical rotation equal
and opposite in sign to that of 1:1 (S)-8/(R)-8. Therefore, (R)-
9/(S)-9 is also of 1:1 composition.
2. Model Study: 2-Methoxyacetyl-1,2-dihydroisoquinal-
donitrile. As a model for use of chiral alkoxyacetyl Reissert
compounds, we prepared 2-methoxyacetyl-1,2-dihydroisoquinal-
donitrile (1a, R ) CH2OCH3), whose proton NMR spectrum
revealed H1 as a broad singlet at 6.65 ppm, H3 as a broadened
doublet at 6.90 ppm (J3,4 ) 8 Hz, J1-3 ∼ 1 Hz), and H4 as a
doublet at 6.15 ppm (J3,4 ) 8 Hz); the amide isomers were not
detected at 25 °C. The diastereotopic C(dO)CH2O protons of
the methoxyacetyl moiety produced an AB quartet.
3. 2-l-Menthoxyacetyl-1,2-dihydroisoquinaldonitrile (10).
l-(-)-Menthoxyacetyl chloride17 yielded Reissert compounds
(R)-10/(S)-10 (Scheme 5), whose proton NMR spectrum (Figure
3b) contained two peaks for H1 at 6.58 and 6.63 ppm of nearly
equal (47:53) proportion. For H4, doublets (J3,4 ) 8 Hz) were
observed at 6.08 and 6.11 ppm. H3 appeared as two doublets at
NMR analyses were recently conducted in toluene-d8 in order
to observe aromatic solvent induced shifts to confirm these
assignments. Protons cis to the carbonyl moieties of the urethane
linkage are expected to undergo small downfield or perhaps
upfield shifts upon switching from CDCl3 to toluene-d8, whereas
protons trans to the carbonyl oxygen are expected to undergo
large upfield shifts.16 At -20 °C in toluene-d8 the minor pair
(37%) of doublets for H3 shifts upfield 0.47 ppm (with respect
to its position in CDCl3 at -20 °C), while the major pair (63%)
of H3 doublets moves upfield by 0.27 ppm (Figure 2), indicating
that the former correspond to the (E)-urethanes and the latter
to the (Z)-urethanes (consistent with our deduction based on
chemical shift patterns of other Reissert compounds). H1 appears
as three distinct peaks at 6.09, 6.03, and 5.77 ppm in a ratio of
30:33:37; due to preferential solvation of the partially positive
nitrogen atom (a consequence of the resonance contribution of
the dN+dC(O-)- structure) by the toluene,16 now the (Z)-
urethane isomers (63%) are resolved as the downfield pair of
H1 peaks with upfield shifts of only 0.35 and 0.41 ppm,
respectively, while the H1 signals for both (E)-urethanes are
now merged into the peak at 5.77 ppm (37%), representing shifts
of 0.52 and 0.46 ppm. Thus, the large H1 signal at 6.43 ppm at
-20 °C in CDCl3 (Figure 1c) includes the (Z)-urethane isomers
of both diastereomers, RE and RZ. These NMR results also
demonstrated that even after 17 years no epimerization occurred.
Therefore, we conclude that in the original sample of 8 the
ratio of R/S diastereomers was 1:1 and the ratio of (E)- to (Z)-
urethane isomers was 4:6 for both diastereomers. The OCH
methine signal of the menthyl group at 4.8 ppm also separated
into four separate multiplets at -20 °C (Figure 2), supporting
the existence of the four stereoisomers in these ratios. Although
chromatography did not result in complete separation of the
diastereomers of 8, changes were observed in the optical
6.95 and 6.98 ppm (J3,4 ) 8 Hz) broadened by coupling (J1,3
∼
1 Hz) to H1. The diastereotopic C(dO)O-CH2 protons of the
menthoxyacetyl moiety of one of the isomers appeared as an
AB quartet centered at 4.31 ppm; the other C(dO)OCH2 signal
of the menthoxyacetyl moiety was a singlet at 4.34 ppm (Figure
3c). At -20 °C this region became more complex, presumably
FIGURE 3. Partial 270 MHz 1H NMR spectra of 2-l-menthoxyacetyl-
1,2-dihydroisoquinaldonitrile [(R)-10/(S)-10] at 25 °C in CDCl3: (a)
bottom, region from 6.0 to 7.4 ppm after chromatography; (b) middle,
region from 6.0 to 7.0 ppm, as synthesized; (c) top, region from 4.1 to
4.5 ppm as synthesized. The peak at ca. 7.27 ppm in (a) is due to CHCl3.
1
FIGURE 2. Partial 400 MHz H NMR spectrum of 2-l-menthoxy-
carbonyl-1,2-dihydroisoquinaldonitrile [1:1 (R)-8/(S)-8] in toluene-d8
at -20 °C.
5762 J. Org. Chem., Vol. 72, No. 15, 2007

Reissert Compounds Bearing Chiral Substituents
SCHEME 7. Reactions of Chiral Reissert Compounds 8-11 with Pivaldehyde via the Corresponding Anions
in part due to the resolution of amide isomers, and revealed the
former C(dO)OCH2 singlet as a closely spaced (0.01 ppm)
equal pair of singlets; corresponding minor (10%) signals also
appeared for H1, H3, and H4. Aromatic solvent induced shift
(ASIS) studies16 in deuterated toluene showed that the two H1
signals at ambient temperature were not from different amide
isomers; from the shifts (0.25 upfield for H1, nearly zero for
H3) it was concluded that the (E)-amide form predominates in
both time averaged diastereomers, even at -20 °C. The
diastereomers (R)-10 and (S)-10 were both formed predomi-
nantly in the (E)-amide configuration. It appears from modeling
that this unusual preference for the E-isomer may arise, in part,
from hydrogen bonding between H1 and the menthoxy oxygen
atom, forming a six-membered ring (see Supporting Information,
Figure S31).
The mixture of (R)-10 and (S)-10 was chromatographed on
silica gel. The ratio of the two NMR peaks for H1 at 6.58 and
6.63 δ changed from 47:53 (Figure 3b) to 65:35 (Figure 3a) in
the first fraction, respectively. This was accompanied by similar
changes in the ratio of doublets for protons H3 and H4 and the
AB patterns of the C(dO)O-CH2 protons. These results
confirmed that the two diastereomers were responsible for signal
doubling. These changes are attributed to separation of the
diastereomers and not to epimerization.
4. 2-Cholesteryloxycarbonyl-1,2-dihydroisoquinaldoni-
triles (11). 1H NMR and HPLC analyses demonstrated that the
chemically pure cholesteryl chloroformate-based isoquinoline
Reissert compounds 11 were a 57:43 mixture of diastereomers,
basically unchanged from the crude product. Recrystallization
from ethyl acetate followed by separation of the diastereomers
with the help of forceps and a lens (a` la Pasteur) and further
recrystallizations afforded both diastereomers in their pure
forms, as confirmed by HPLC (see Supporting Information,
Figure S2). X-ray structural analysis (see Supporting Informa-
tion, Figure S3) showed that the minor diastereomer was (S)-
11 and, by inference, the predominant diastereomer was (R)-
11.
and to produce the carbonates in the cases of 8, 9, and 11) in
DMF as indicated in Scheme 7 and summarized in Table 2.
1. Reaction of 2-l-Menthoxycarbonyl-1,2-dihydroisoquinal-
donitrile (8) with Pivaldehyde. The crude product carbonates
(R)-12/(S)-12 from the 1:1 mixture of (S)-8 and (R)-8 were
examined using HPLC on a Pirkle phenylglycine column, which
revealed two peaks with retention times of 371 (82%) and 414
s (18%) (see Supporting Information, Figure S4). The proton
NMR spectrum (Figure 4a) of the crude product 12 contained
two peaks at 6.18 and 6.24 ppm for the methine proton (HR) at
the newly formed carbinyl center in a ratio of 77:23. After a
single recrystallization from hexanes, the proton NMR spectrum
(Figure 4b) of the compound exhibited only one peak for the
methine proton (HR) at 6.18 ppm; the HPLC trace exhibited
only the peak at 371 s (see Supporting Information, Figure S4).
The X-ray structure of this pure major diastereomer (see
Supporting Information, Figure S5) established the S-configu-
ration of the newly formed stereocenter by reference to the
known configurations of the l-menthyl stereocenters.
Reactions of 8 with aromatic aldehydes under similar
conditions afforded carbonates and esters with up to 66:34
diastereoselectivity (see Supporting Information, Table S1,
Figures S6 and S7); the resultant compounds were found to
epimerize quite rapidly (hours-days) even in the solid state
(presumably via SN1 processes since these esters are doubly
benzylic).
2. Reaction of 2-d-Menthoxycarbonyl-1,2-dihydroiso-
quinaldonitrile (9) with Pivaldehyde. The 1:1 R/S mixture of
the d-menthyl Reissert compound 9 led to a 77:23 (by 1H NMR)
mixture of (R)-13/(S)-13. A single recrystallization produced
TABLE 2. Reactions of Diastereomeric Reissert Compounds with
Pivaldehyde
Reissert compd
product
yield (%)
diastereomeric ratio
1:1 (R)-8/(S)-8
1:1 (R)-9/(S)-9
47:53 (R)-10/(S)-10
(S)-11
12
13
14
15
100
100
97
77:23 S/R,a 82:18 S/Rb
77:23 R/Sa
50:50c,d
100
52:48c,e
B. Synthesis of Diastereomeric Esters and Carbonates by
Condensation of Reissert Compounds with Aldehydes. These
reactions were initially carried out with pivaldehyde using NaH
as the base at -40 °C (to avoid formation of cyclic urethanes
a Determined by integration of the HR signals in the 1H proton NMR
spectrum (Figure 4a). b Determined by HPLC with a Pirkle phenylglycine
column (99:1 hexane/isopropanol, 1 mL/min); listed in order of elution (see
Supporting Information, Figure S4). The identity of the major S-isomer
was established by X-ray crystallography (see Supporting Information,
Figure S5). c Determined by integration of the HR signals in the 1H proton
NMR spectrum. d Confirmed by HPLC with a Pirkle phenylglycine column
(99:1 hexane/isopropanol, 1 mL/min); listed in order of elution. e Confir-
med by HPLC with a Pirkle phenylglycine column (99:1 hexane/isopropanol,
1 mL/min); listed in order of elution (see Supporting Information, Figure
S8).
(16) (a) Hatton, J. V.; Edwards, R. E. Mol. Phys. 1962, 5, 139-152. (b)
Shvo, Y.; Taylor, E. C.; Mislow, K.; Raban, M. J. Am. Chem. Soc. 1967,
89, 4910-4917. (c) Monro, A. M.; Sewell, M. J. Tetrahedron Lett. 1969,
595-598. (d) Stewart, W. E.; Siddall, T. H., III. Chem. ReV. 1970, 70,
517-551.
(17) Leffler, M. T.; Calkins, A. E. Organic Synthesis; Wiley: New York,
1955; Coll. Vol. 3; (a) p 544, (b) p 547.
J. Org. Chem, Vol. 72, No. 15, 2007 5763

Gibson et al.
4. Reaction of 2-l-Menthoxyacetyl-1,2-dihydroisoquinal-
donitrile (10) with Pivaldehyde. The diastereomeric esters (R)-
14/(S)-14 from 1:1 (R)-10/(S)-10 and pivaldehyde were formed
with no diastereoselectivity as determined by the NMR analysis
of the methine proton (HR) singlets (6.48 and 6.53 ppm) and
the four sets of doublets of equal intensity observed for H5 and
H8 in the range 8.3-8.7 ppm. HPLC analysis confirmed this
composition. The product was passed through a silica gel
column, and the ratio of diastereomers changed to 70:30. In
the proton NMR spectrum the downfield HR signal (6.53 ppm)
predominated; likewise the downfield signals for H5 and H8 were
enhanced. A second sample purified by simply washing the
crude material with hexanes was found to be a 90:10 mixture
of diastereomers by HPLC. These changes in diastereomeric
ratio are again attributed to selective separation of the diaster-
eomers and not to epimerization, since there was no evidence
for epimerization over time.
5. Reaction of 2-Cholesteryloxycarbonyl-1-,2-dihydroiso-
quinaldonitrile [(S)-11] with Pivaldehyde. From diastereo-
merically pure (S)-11 and pivaldehyde, carbonate 15 was isolated
in quantitative yield. Both 1H NMR and HPLC (see Supporting
Information, Figure S8) demonstrated that there was no stereo-
selectivity in this reaction.
1
FIGURE 4. 270 MHz H NMR spectra of 1-isoquinolyl tert-butyl
D. Synthesis of Optically Pure 1-isoquinolyl tert-Butyl
Carbinols [(R)-16, (S)-16]. A 10-fold excess of base and a 2.5
h reaction period allowed hydrolysis of the pure diastereomeric
carbonate (S)-12 to produce 99% optically pure S-(-)-1-
isoquinolyl tert-butyl carbinol [(S)-16] (Scheme 8). The optical
purity was determined using quinine as a chiral solvating agent
(CSA)18 (see Supporting Information, Figures S9 and S10). A
sample of 99% diastereomerically pure carbonate (R)-13 was
hydrolyzed to form R-(+)-1-isoquinolyl tert-butyl carbinol [(R)-
16] with 98% optical purity as determined by use of quinine as
a CSA.
carbinyl l-menthyl carbonate (12) in CDCl3 at 25 °C: (a) bottom, as
synthesized mixture of (S)-12 and (R)-12; (b) top, pure (S)-12 obtained
after one recrystallization.
SCHEME 8. Hydrolysis of 1-Isoquinolyl tert-Butyl Carbinyl
Menthyl Carbonates to 1-Isoquinolyl tert-Butyl Carbinols
E. Synthesis of Diastereomeric Reissert Compounds from
6,7-Dimethoxy-3,4-dihydroisoquinoline. Using standard condi-
tions, we prepared the dihydro-Reissert compounds 18-21 from
6,7-dimethoxy-3,4-dihydroisoquinoline and chiral acid chlorides
(Scheme 9), and the results are summarized in Table 3.
99% diastereomerically pure R-(+)-1-isoquinolyl tert-butyl
carbinyl menthyl carbonate [(R)-13].
3. Reaction of Methoxyacetyl-1,2-dihydroisoquinaldoni-
trile (1a, R ) CH2OCH3) with Pivaldehyde. In a model
reaction of 1a (R ) CH2OCH3) with pivaldehyde, product 3
(R ) CH2OCH3, R′ ) t-Bu) was obtained in quantitative yield.
In the NMR spectrum the methine proton (HR) singlet appeared
at 6.5 ppm. In the aromatic region one doublet each [8.6 ppm
(J ) 6 Hz), 8.4 ppm (J ) 7 Hz)] was found for the aromatic
protons H5 and H8. The diastereotopic C(dO)OCH2 protons of
the methoxyacetyl group were observed as an AB quartet
centered at 4.2 ppm.
F. Alkylation of Diastereomeric Reissert Compounds.
Alkylation reactions of diastereomeric Reissert compounds 8
and 11 (Scheme 10) are summarized in Table 4. Benzylation
of 8 proceeded with modest diastereoselectivity to produce 22c.
However, with methyl iodide neither 8 nor pure (S)-11 afforded
any selectivity. This finding for 22a from 8 contradicts the recent
claim of “excellent yield and stereoselectivity” for this particular
alkylation reaction using LDA as the base.13
SCHEME 9. Synthesis of Dihydro-Reissert Compounds 18-21 from 6,7-Dimethoxy-3,4-Dihydroisoquinoline (17)
5764 J. Org. Chem., Vol. 72, No. 15, 2007

Reissert Compounds Bearing Chiral Substituents
TABLE 3. Synthesis of Diastereomeric Dihydro-Reissert
Compounds
TABLE 4. Alkylation of Diastereomeric Isoquinoline Reissert
Compoundsa
Reissert compd
yield (%)
diastereomeric ratio
Reissert compd alkyl halide product yield (%) diastereomericratio
18
19
37
77
51
26
80
66
50:50a
65:35b
100
1:1(S)-8/(R)-8
1:1(S)-8/(R)-8
1:1(S)-8/(R)-8
1:1(S)-8/(R)-8
(S)-11
CH3I
22a
22b
22b
22c
23a
92
10
90
72
100
50:50b,c
36:64b
n-BuCl
n-BuBr
C6H5CH2I
CH3I
(S)-19c
(R)-19c
20
36:64b,d
72:28e
100
20:80d
?
55:45b,f
21
a In DMF at -40 °C using NaH as the base. b By HPLC with a Pirkle
phenylglycine column (99:1 hexane/isopropanol, 1 mL/min); listed in order
of elution. c See Supporting Information, Figure S11. d See Supporting
a Determined by integrations of methyl triplets at 0.85 and 0.95 ppm
and methyl doublets at 1.13 and 1.18 ppm in the H proton NMR spectra
1
1
in CDCl3 (see Supporting Information, Figure S15) and toluene-d8 (see
Supporting Information, Figure S16), and confirmed by X-ray crystal-
lography (see Supporting Information, Figure S17). b Mixture confirmed
qualitatively by HPLC with a Pirkle phenylglycine column (99:1 hexane/
isopropanol, 1 mL/min); listed in order of elution (see Supporting
Information, Figure S18). c The diastereomers of 19 were easily separated
by recrystallization; the identity of the major isomer was established by
X-ray crystallography (see Supporting Information, Figure S21). d Deter-
mined by HPLC with a normal phase silica column (85:15 hexane/ethyl
acetate, 1 mL/min); listed in order of elution (see Supporting Information,
Figure S22).
Information, Figure S12. e By integration of H NMR spectrum; arbitrary
designations. f See Supporting Information, Figure S13.
lated, apparently a result of removal of HCN from 27 (Scheme
12), perhaps by elimination of HCN from the 4-anion of the
1,4-dihydro-isomer of 27; there is some precedent for such
processes in dihydroisoquinolines.20
Compounds 25a, 25c, and 26a were prepared by cyanoacy-
lation21 of the corresponding 1-alkyl-6,7-dimethoxy-3,4-dihy-
droisoquinolines (Scheme 13) in hopes that greater selectivity
could be achieved; however, this proved not to be the case (see
Supporting Information).
Alkylation reactions of the dihydro-Reissert compounds 18-
21 were also examined (Scheme 11). The results (Table 5) reveal
modest diastereoselectivty in the case of 9-phenylmenthyl
product 26a. Pure diastereomer (S)-19 was methylated with
some selectivity in formation of 25a. With isopropyl iodide 25b
was formed nondiastereoselectively. Alkylation of (S)-19 with
benzyl iodide proceeded in high yield, but the diastereomeric
ratio of 25c could not be determined.
G. Nature of the Reissert Anions. There are three possible
geometries for the anions of isoquinoline Reissert compounds:
(1) planar sp2 carbon at C1 (i. e., through ArC(N)dCdN-) as
is common for benzylic22 and other23 carbanions, (2) tetrahedral/
pyramidal C1 but equilibrating,24 and 3) tetrahedral/pyramidal
C1 but not equilibrating.
As with other N-sulfonyl Reissert compounds19 attempted
methylation of 21 led to elimination of the sulfinate moiety from
the Reissert anion and formation of the 1-cyano-3,4-dihydroiso-
quinoline 27 (Scheme 12). Upon treatment with NaH in DMF,
the fully aromatized 6,7-dimethoxyisoquinoline (28) was iso-
The results described above and formation of mixed diaster-
eomeric products from quenching diastereomerically pure
SCHEME 10. Alkylation of Chiral Reissert Compounds 8 and 11
SCHEME 11. Alkylation of Chiral Dihydro-Reissert Compounds 18-20
J. Org. Chem, Vol. 72, No. 15, 2007 5765

Gibson et al.
TABLE 5. Alkylation of Diastereomeric Dihydro-Reissert Compounds
Reissert compd
RX
conditions
product
yield (%)
diasteromeric ratio
1:1 (R)-18/(S)-18
(S)-19
(S)-19
(S)-19
(S)-19
CH3I
CH3I
CH3I
(CH3)2CHI
(CH3)2CHI
C6H5CH2I
CH3I
n-BuLi/THF, -100 °C
NaH/DMF, 0 °C
24a
25a
25a
25b
25b
25c
26a
h
90
83
100
100
98
50:50a,b
36:64c
54:46c
50:50e
∼50:50f
??
n-BuLi/THF, -100 °Cd
NaH/DMF, 0 °C
LDA/THF, -78 °C
NaH/DMF, 25 °C
NaH/DMF, 25 °C
NaH/DMF, -40, 25 °C
(S)-19
89
100
4:1 (R)-20/(S)-20 g
21
67:33c
CH3I
a Determined by integration of the pair of 1-methyl singlets at ∼1.9 ppm in the 1H NMR spectrum of the product in CDCl3 (see Supporting Information,
Figures S24 and S25). b Confirmed by integration of the pair of R-methyl doublets at 1.17 and 1.20 ppm in the 1H NMR spectrum of the product in CDCl3
(see Supporting Information, Figure S25) and the X-ray crystal structure (see Supporting Information, Figure S26). c Determined by integration of the pair
1
of 1-methyl singlets at ∼1.9 ppm in the H NMR spectrum of the product in toluene-d8 (see Supporting Information, Figures S27 and S29); configuration
of major diastereomer unknown. d See Supporting Information for procedure. e Established by X-ray crystallography (see Supporting Information, Figure
S28). [R]D25 ) -46.2 (c ) 15.6, CH2Cl2). f See Supporting Information. [R]D25 ) -53.1 (c ) 0.700, CHCl3). g Arbitrary designation; configuration of major
diastereomer unknown. h No alkylation occurred; see text and Supporting Information.
SCHEME 12. Transformations of Camphorsulfonyl
Dihydro-Reissert Compound 21
NMR was used to determine the ratio of diastereomers (1:1 R/S)
and also the ratio of (E)- to (Z)-urethane rotational isomers (4:
6) of 2-l-menthoxycarbonyl-1,2-dihydroisoquinaldonitrile (8).
Thus, contrary to a recent report,13 this reaction is not >95%
diastereoselective. Notably, 2-cholesteryloxycarbonyl-1,2-dihy-
droisoquinaldonitriles (11) were similarly produced as a mixture
of diastereomers, 41% S and 59% R, which could be morpho-
logically separated quite easily. Similarly, the diastereomers of
2-l-menthoxycarbonyl-1,2,3,4-tetrahydroisoquinaldonitrile (19)
were readily separated and purified.
SCHEME 13. Cyanoacylation of
1-Alkyl-6,7-Dimethoxy-3,4-Dihydroisoquinolines as a Route
to 24-26
The reaction of 1:1 (S)-8/(R)-8 with pivaldehyde gave the
carbonate 12, whose major (82%) diastereomer (S)-12 was easily
separated from the minor diastereomer (R)-12 (18%) by a single
recrystallization from hexanes. Diastereomerically pure (S)-12
was hydrolyzed to the 99% enantiomerically pure 1-isoquinolyl
tert-butyl carbinol [(S)-16]. Starting from the d-menthyl Reissert
compounds (R)-9 and (S)-9, we synthesized (R)-1-isoquinolyl
tert-butyl carbinol [(R)-16] with 98% optical purity in an ana-
logous fashion. Aromatic aldehydes react with similar stereo-
selectivities, but the products epimerize rather rapidly. 2-Cho-
lesteryloxycarbonyl-1,2-dihydroisoquinaldonitrile [(S)-11], as the
pure diastereomer, in condensation with pivaldehyde was totally
nonselective, yielding equal amounts of the two diastereomers.
The mixture (1:1) of diastereomers of 2-l-menthoxycarbonyl-
1,2-dihydroisoquinaldonitrile (8) was alkylated with butyl
and benzyl halides with modest diastereoselectivities (Table 4).
With methyl iodide no selectivity was observed, contrary to a
recent claim.13 However, methylation of dihydro-Reissert
compounds 18-20 proceeded with modest selectivities, up to
2:1 (Table 5).
Reissert anions with D2O or H2O (see Supporting Information)
clearly demonstrate that nonequilibrating anions can be ruled
out. The modest stereoselectivity observed in some cases can
be attributed to the effects of the chiral auxiliary in terms of
selective blocking of one face of the carbanion (see Supporting
Information, Figure S32).
Conclusions
Reissert compounds bearing chiral substituents were prepared
from isoquinoline (8-11) and 6,7-dimethoxy-3,4-dihydroiso-
quinoline (18-21) (Tables 1 and 3). Low-temperature proton
The lack of highly selective reactions of these Reissert anions
is explained by the fact that they are not static tetrahedral species
but are rather either planar or equilibrating tetrahedral species.
(18) Rosini, C.; Uccello-Barretta, G.; Pini, D.; Abete, C.; Salvadori, P.
J. Org. Chem. 1988, 53, 4579-4581.
Experimental Section
(19) Wefer, J. M.; Catala, A.; Popp, F. D. J. Org. Chem. 1965, 30, 3075-
7.
Caution: Trimethylsilyl cyanide (TMSCN) is toxic and should
be used in an efficient fume hood.
(20) Li, W.-D. Z.; Yang, H. Tetrahedron 2005, 61, 5037-5042.
(21) Berg, M. A. G.; Gibson, H. W. J. Org. Chem. 1992, 57, 748-750.
(22) (a) Brooks, J. J.; Stucky, G. D. J. Am. Chem. Soc. 1972, 94, 7333-
7338. (b) Peoples, P. R.; Grutzner, J. B. J. Am. Chem. Soc. 1980, 102,
4709-4715. (c) Jernigan, M. T.; Eliel, E. L. J. Am. Chem. Soc. 1995, 117,
9638-9644. (d) Enders, D.; Kirchoff, J.; Gerdes, P.; Mannes, D.; Raabe,
G.; Runsink, J.; Boche, G.; Marsch, M.; Ahlbrecht, H.; Sommer, H. Eur.
J. Org. Chem. 1998, 63-72. (e) Binev, Y. I.; Petrova, R. R.; Tsenov, J. A.;
Binev, I. G. J. Mol. Struct. 2000, 516, 23-29.
2-l-Menthoxycarbonyl-1,2-dihydroisoquinaldonitrile (8). Gen-
eral Method for Reissert Compound Synthesis. To a stirred
solution (0 °C, N2) of isoquinoline (9.68 g, 75.0 mmol) in methylene
chloride (150 mL), was added l-menthyl chloroformate (18.04 g,
82.5 mmol) followed after 15 min by TMSCN (7.81 g, 76.0 mmol).
The reaction was monitored by TLC (silica gel, EtOAc/hexanes,
2:8). Stirring was continued for 48 h at rt, and the reaction was
terminated by the addition of water (150 mL) and stirring overnight.
The organic layer was separated and washed with water (2 × 30
mL), 10% HCl (2 × 20 mL), saturated NaHCO3 (2 × 30 mL), and
(23) (a) Zimmerman, H. E.; Ignatchenko, A. J. Org. Chem. 1999, 64,
6635-6645. (b) Karazi, Y.; Vertgoten, G.; Supateanu, J. Mol. Structure
1999, 476, 121-131.
(24) Carlier, P. Chirality 2003, 15, 340-347.
5766 J. Org. Chem., Vol. 72, No. 15, 2007

Reissert Compounds Bearing Chiral Substituents
water (2 × 30 mL). It was dried over Na2SO4 and concentrated by
2-Cholesteryloxycarbonyl-1,2-dihydroisoquinaldonitrile (11).
Isoquinoline and cholesteryl chloroformate gave the crude product
(91%) as a cream colored solid, mp 167-173 °C, [R]D25 ) -2.32
(c ) 2.76, CH2Cl2). HPLC on a Pirkle column (99:1 hexanes/
isopropanol, flow rate 1.0 mL/min) gave signals at 12.6 and 13.5
min with nearly baseline separation in a ratio of 41:59, respectively
(see Supporting Information, Figure S2). Two recrystallizations
from ethyl acetate produced a sample with two types of crystals;
these were separated by means of a magnifiying glass and forceps
and recrystallized individually to diastereomeric purity (see Sup-
porting Information, Figure S2). The sample with the lower retention
time on HPLC had mp 184-186 °C and [R]D25 ) -95.5 (c ) 2.41,
CH2Cl2); X-ray crystallography (see Supporting Information, Figure
S3) demonstrated that this was the S-diastereomer. The R-
diastereomer had mp 200-201 °C and [R]D25 ) +80.9 (c ) 2.75,
CH2Cl2). FTIR (KBr): ν 2950 (C-H), 1715 (CdO), and 1150 (C-
rotary evaporation to give the crude product (27.17 g, 96%).
25
Analytically pure product, mp 96-97 °C, [R]D ) -63.5 (c )
1.53, CH2Cl2), was obtained by three recrystallizations from
hexanes. HPLC on a Pirkle phenylglycine column gave one signal
at 10.6 min (99:1 hexanes/isopropanol, flow rate 1 mL/min). HPLC
on a Chiralcel OD column produced one signal at 22 min (95:5
hexanes/isopropanol, flow rate 0.25 mL/min). FTIR: ν 2950
1
(C-H), 1713 (CdO), and 1150 (C-O) cm-1. H NMR (CDCl3,
-20 °C, see Figure 1c): δ 0.5-2.2 (m, 18H), 4.60-4.90 (m, 1H,
OCH), 6.03 (d, J ) 8 Hz, 0.2H, H4), 6.04 (d, J ) 8 Hz, 0.2H, H4),
6.07 (d, J ) 8 Hz, 0.3H, H4), 6.08 (d, J ) 8 Hz, 0.3H, H4), 6.23
(s, 0.2H, H1), 6.28 (s, 0.2H, H1), 6.43 (s, 0.6H, H1), 6.87 (d, J )
8 Hz, 0.3H, H3), 6.92 (d, J ) 8 Hz, 0.3H, H3), 7.03 (d, J ) 8 Hz,
0.2H, H3), 7.04 (d, J ) 8 Hz, 0.2H, H3), 7.15 (d, J ) 8 Hz, 1H),
7.20-7.38 (m, 3 H). 13C NMR (CDCl3): δ 16.4, 16.6, 20.7, 21.8,
23.7, 23.9, 26.4, 26.8, 31.5, 34.2, 41.0, 41.3, 46.3, 47.4, 78.5, 108.6,
116.5, 124.1, 124.4, 125.7, 126.5, 126.8, 128.0, 130.0, 130.5, 151.9.
LR EIMS m/z: 338 (M+, 7%), 183 (M+ - C10H7N2, 12%) 156
(M+ - C11H18O2, 100%). HRMS-FAB (NBA-PEG) m/z: 338.1983
(calcd For M+ 338.1994). Anal. Calcd for C21H26N2O2: C, 74.52;
H, 7.74; N, 8.28. Found: C, 74.51; H, 7.74; N, 8.30. Careful column
chromatography of 1.0 g of this mixture on 100 g of silica gel by
elution with 5% ethyl acetate in hexanes afforded 22 fractions with
1
O) cm-1. H NMR (CDCl3): δ 0.6-2.1 (m, 43H), 4.70 (m, 1H,
OCH), 5.44 (br s, 1H, dCH-), 6.00 (overlapping d, J ) 7.4 Hz,
1H, H4), 6.22 (br s, 0.45H, H1), 6.37 (br s, 0.55H, H1), 6.87 (d, J
) 7.4 Hz, 0.55H, H3), 6.99 (d, J ) 7.4 Hz, 0.45H, H3), 7.16 (d, J
) 7.3 Hz, 1H, H5), 7.20-7.38 (m, 3H). Anal. Calcd for
C38H52N2O2: C, 80.23; H, 9.22; N, 4.92. Found: C, 80.12; H, 9.38;
N 4.81.
S-(-)-1-Isoquinolyl tert-Butyl Carbinyl l-Menthyl Carbonate
[(S)-12]. General Method for Reactions of Reissert Compounds
with Pivaldehyde and Alkyl Halides. A well stirred solution of
1:1 mixture of diastereomers of the Reissert compound 8 (500 mg,
1.3 mmol) and pivaldehyde (0.17 mL, 1.6 mmol) in DMF (15 mL)
was cooled to -40 °C under nitrogen. After addition of 80% NaH
(80 mg, 2.7 mmol), the mixture was allowed to stir for 5 h and
quenched into water (100 mL). The ether extract (3 × 20 mL) was
washed with water (4 × 20 mL) and evaporated to yield the crude
product: 516 mg (100%), mp 90-100 °C, and [R]D25 ) -42.5 (c
) 2.00, CH2Cl2). HPLC was performed on a Pirkle covalent
phenylglycine column (99:1 hexanes/isopropanol, flow rate 1 mL/
min): two peaks, one at 371 s and another at 414 s (ratio 82:18,
see Supporting Information, Figure S4). Upon recrystallization
from hexanes once, the S-enantiomer was isolated with mp 122-
25
[R]D ranging from -58.7 to -22.5 (c ) 1.1-1.5, CH2Cl2).
Automated flash chromatography yielded fractions with quantita-
tively different NMR spectra (see Supporting Information, Figure
S1), but neither pure diastereomer was isolated.
2-d-Menthoxycarbonyl-1,2-dihydroisoquinaldonitrile (9). The
above method with isoquinoline and d-(+)-menthyl chloroformate
gave a 98% yield of crude product. Pure product, mp 96-97 °C,
25
[R]D ) +63.4 (c ) 2.00, CH2Cl2), was obtained by three
recrystallizations from hexanes. Spectral data of 9 were identical
to those of 8.
2-Methoxyacetyl-1,2-dihydroisoquinaldonitrile (1, R ) CH2-
OCH3). The method above using isoquinoline and methoxyacetyl
chloride afforded a quantitative yield. The product was purified by
column chromatography on silica gel (5:95 EtOAc/hexanes) fol-
lowed by three recrystallizations from EtOAc/hexanes. mp 103-
104 °C. FTIR (KBr): ν 2957 (C-H), 1680 (CdO), 1630 (Ar C-H),
25
123 °C and [R]D ) -35.5 (c ) 1.78, CH2Cl2). HPLC for the
pure compound showed only the peak at 371 s (see Supporting
Information, Figure S4). X-ray crystallography (see Supporting
Information, Figure S5) showed the configuration at C1 to be S.
FTIR (KBr): ν 2887-2964 (C-H), 1779 (CdO), 1170 (C-O),
1166, and 1128 cm-1. 1H NMR (CDCl3, Figure 4b, pure diastere-
omer): δ 0.44 (d, J ) 7 Hz, 3 H, CH3), 0.80 (d, J ) 7 Hz, 3H,
CH3), 0.88 (d, J ) 7 Hz, 3H, CH3), 1.09 [s, 9 H, C(CH3)3], 0.70-
2.1 (underlying m, 9 H), 4.32 (m, 1H, ring OCH), 6.18 (s, 1H,
IQ-CHO) [in the mixture of diastereomers: 6.18 (s, 0.70 H, IQ-
CHO), 6.24 (s, 0.30 H, IQ-CHO)], 7.58 (d, J ) 8 Hz, 1H), 7.60-
7.70 (m, 2H), 7.83 (d, J ) 8 Hz, 1H), 8.40 (d, J ) 8 Hz, 1H), 8.55
(d, J ) 8 Hz, 1H). Anal. Calcd for C25H35NO3: C, 75.46; H, 8.87;
N, 3.52. Found: C, 75.44; H, 8.90; N, 3.51.
1
1344, and 1130 cm-1. H NMR (CDCl3): δ 3.5 (s, 3H), 4.23 and
4.41 (1H each, d, J ) 14 Hz), 6.10 (d, J ) 8 Hz, 1H), 6.65 (s, 1H),
6.90 (d, J ) 8 Hz, 1H), 7.2-7.5 (m, 4H). Anal. Calcd for
C13H12N2O2: C, 68.40; H, 5.30; N, 12.28. Found: C, 68.48; H,
5.32; N, 12.30.
2-l-Menthoxyacetyl-1,2-dihydroisoquinaldonitrile [(R)-10/(S)-
10]. Application of the above procedure to isoquinoline and
l-(-)-menthoxyacetyl chloride (see Supporting Information) pro-
duced a 67% yield of an oily product. The ratio of the diastereomers
in the crude compound was 1:1 (by NMR). The product was
dissolved in EtOAc, and the solution treated twice with activated
charcoal and filtered through Celite. The compound was then
subjected to silica gel column chromatography, eluting consecu-
tively with hexanes, hexanes/EtOAc (99.75:0.25), and hexanes/
EtOAc (99.50:0.50). This resulted in partial separation of the
diastereomers. The first fraction (mp 79-81 °C) was a 65:35
mixture of diastereomers as deduced from the NMR spectrum
(Figure 3a). The ratio then went to 48:52 within a few fractions
with mp 79-81 °C and [R]D25 ) -51.4 (c ) 2.0, CH2Cl2). FTIR:
ν 2960-2860 (C-H), 1738 (CdO), 1630 (Ar C-H), 1450, 1221,
R-(+)-1-Isoquinolyl tert-Butyl Carbinyl d-Menthyl Carbo-
nate [(R)-13]. From the 50:50 mixture of R/S diastereomers of
Reissert compound 9 and pivaldehyde (R)-13 was isolated
25
(70%) and purified analogously, with mp 122-123 °C and [R]D
) +35.5 (c ) 1.50, CH2Cl2). Spectral data were identical to those
of (S)-12.
1-Isoquinolyl tert-Butyl Carbinyl Methoxyacetate (3, R )
CH2OCH3, R′ ) tert-Bu). Reissert compound 1, R ) CH2OCH3,
and pivaldehyde produced (98%) the ester, which was purified
by silica gel chromatography (90:10 hexanes/EtOAc). mp 116-
117 °C. FTIR (neat): ν 2960, 2932, 1750, 1627, 1382, 1273, and
1
and 1124 (C-O) cm-1. H NMR (∼50:50 sample, CDCl3, -20
°C, Figure 3b): δ 0.60-2.4 (m, 17H), 3.22 (q, J ) 12 Hz, 0.5H,
OCH), 3.26 (q, J ) 12 Hz, 0.5H, OCH), 4.27 and 4.42 (0.5H each,
J ) 14 Hz, COCH2), 4.37 (s, 0.5H, COCH2), 4.38 (s, 0.5H,
COCH2), 6.13 (d, J ) 8 Hz, 0.5H, H4), 6.14 (d, J ) 8 Hz, 0.5H,
H4), 6.61 (br s, 0.5 H, H1), 6.64 (br s, 0.5H, H1), 6.90 (dd, J ) 1
Hz, 8; 0.5H, H3), 6.91 (dd, J ) 1 Hz, 8; 0.5H, H3), 7.15-7.5 (m,
3H). Anal. Calcd for C22H28N2O2‚0.25CH3COOCH2CH3: C, 73.76;
H, 8.08; N, 7.48. Found: C, 73.35; H, 7.74; N, 7.56.
1
1128 cm-1. H NMR (CDCl3): δ 1.10 (s, 9H), 3.40 (s, 3H), 4.20
(s, 2H), 6.55 (s, 1H), 7.6-8.05 (m, 4H), 8.40 (d, J ) 8 Hz, 1H),
8.60 (d, J ) 8 Hz, 1H). Because of its instability, we were unable
to obtain a satisfactory elemental analysis.
1-Isoquinolyl tert-Butyl Carbinyl 1-Menthoxyacetate (14). A
1:1 diastereomeric mixture of Reissert compounds (R)-10 and (S)-
J. Org. Chem, Vol. 72, No. 15, 2007 5767

Gibson et al.
10 and pivaldehyde produced a 97% yield of an oil (1:1 S/R by 1H
NMR). Column chromatography on silica gel (9:1 hexanes/EtOAc)
afforded chemically pure product as a clear oil that crystallized
Figure S13) the product was comprised of a 55:45 mixture of the
two diastereomers. A reaction at rt for 20 h led to complete
conversion with formation of the two diastereomeric products in a
25
1
slowly; mp 65-75 °C, [R]D ) -49.0 (c ) 3.3, CH2Cl2), and
55:45 ratio. H NMR (CDCl3): δ 0.60-2.2 (m, 41H, including a
70:30 dr by NMR. HPLC on a Pirkle phenylglycine column (99:1
hexanes/isopropanol, 1 mL/min) gave the major peak at 533 s (71%)
and the minor peak at 550 s (29%). FTIR (neat): ν 2955, 2924,
1756, 1126 cm-1. 1H NMR (CDCl3): δ 0.60-2.30 (m, 27H), 3.20
(m, 1H), 4.24 and 4.38 (0.15H each, d, J ) 14 Hz), 4.34 (s, 0.7H),
6.43 (s, 0.3H), 6.53 (s, 0.7H), 7.65-7.90 (m, 4H), 8.15 (d, J ) 8
Hz, 0.3H), 8.39 (d, J ) 8 Hz, 0.7H), 8.49 (d, J ) 8 Hz, 0.3H),
8.55 (d, J ) 8 Hz, 0.7H). Anal. Calcd for C25H37NO3: C, 75.15;
H, 9.33; N, 3.51. Found: C, 75.17; H, 9.03; N, 3.66.
1-Isoquinolyl tert-Butyl Carbinyl Cholesteryl Carbonate (15).
Conversion of (S)-11 and pivaldehyde to 15 was quantitative. Both
NMR and HPLC analyses (Pirkle phenylglycine column, 99:1
hexanes/isopropanol, 1 mL/min) indicated the two diastereomers
were formed in 52:48 ratio (see Supporting Information, Figure
S8). 1H NMR (CDCl3): δ 0.60-2.5 (m, 52H), 4.30 (m, 1H), 5.27
(d, J ) 7 Hz, 0.5H), 5.29 (d, J ) 7 Hz, 0.5H), 6.20 (s, 1H), 7.5-
7.7 (m, 2H), 7.82 (d, J ) 8 Hz, 1H), 8.35 (d, J ) 8 Hz, 1H), 8.56
(d, J ) 8 Hz, 1H). Recrystallized from acetone, mp 123-124 °C.
Anal. Calcd for C42H61NO3‚1/3H2O: C, 79.57; H, 9.80; N, 2.21.
Found: C, 79.66; H, 9.71; N, 2.18. HRMS-FAB (NBA-PEG) m/z:
628.4742 [calcd for (M + H)+ 628.4730].
sharp singlet at 1.91 ppm), 2.50 (m, 2H), 3.64 (m, 2H), 4.76 (m,
1H), 5.44 (br s, 1H), 5.68 (d, J ) 7 Hz, 1H), 6.87 (d, J ) 8 Hz,
1H), 7.01 (m, 1H), 7.23 (m, 3H), 7.59 (m, 1H). Recrystallized from
acetone, mp 178-180 °C. Anal. Calcd for C39H54N2O2: C, 80.37;
H, 9.34; N, 4.81. Found: C, 80.02; H, 9.22; N, 4.79. HRMS-
FAB (NBA-PEG) m/z: 583.4225 [calcd for [M + H]+ 583.4264].
2-[(S)-R-Methylbutyryl]-1-cyano-6,7-dimethoxy-1,2,3,4-tet-
rahydroisoquinoline (18). General Procedure for Preparation
of Dihydro-Reissert Compounds. To a stirred solution of 6,7-
dimethoxy-3,4-dihydroisoquinoline (17)25 (1.08 g, 5.65 mmol),
TMSCN (0.62 g, 6.2 mmol), and anhyd AlCl3 (0.08 g, 0.6 mmol)
in CH2Cl2 (30 mL) was added (S)-R-methylbutyryl chloride (0.75
g, 6.2 mmol, see Supporting Information). The mixture was stirred
for 5 days. Water (1 mL) was added to the mixture and stirring
continued for 1 day. The organic phase was washed three times
each with H2O, 10% aq HCl, H2O, 10% aq NaOH, H2O, and once
with brine. The CH2Cl2 was removed in vacuo to give 0.64 g (37%
yield) of a yellow solid, which was recrystallized twice from ethanol
and once from ethyl acetate to afford colorless crystals. mp 140-
25
141 °C. [R]D ) +16.7 (c ) 0.773, CHCl3). IR (KBr): ν 2236,
1
1684 cm-1. H NMR: δ 0.85 (t, J ) 7 Hz, 1.5H), 0.95 (t, J ) 7
S-(-)-1-Isoquinolyl tert-Butyl Carbinol [(S)-16]. A stirred
solution of 318 mg (0.80 mmol) of S-(-)-isoquinolyl tert-butyl
l-menthyl carbonate [(S)-12] and 324 mg (8.0 mmol) of NaOH in
25 mL each of water, THF, and ethanol was heated at reflux for
2.5 h (monitored by TLC, 1:1 ethyl acetate/hexanes), cooled, and
extracted with ether. The ether extract was in turn extracted with
10% HCl, and the aqueous solution was made basic (pH 10) by
addition of NaOH and extracted with ether. The ethereal extract
was washed with water and brine and dried over sodium sulfate.
Removal of the ether under vacuum yielded 90 mg (80%) of the
alcohol, mp 100-101 °C, [R]D25 ) -70.6 (c ) 1.17, CH2Cl2), after
two recrystallizations from EtOAc/hexanes. Optical purity was
established by utilization of quinine as a chiral solvating agent18 in
1H NMR as described in the Supporting Information (Figures S9
and S10). FTIR (KBr): ν 3300-3500 (O-H), 2810-2600 (C-
Hz, 1.5H), 1.13 (d, J ) 7 Hz, 1.5H), 1.18 (d, J ) 7 Hz, 1.5H),
1.47 (m, 1H), 1.73 (m, 1H), 2.70 (m, 1H), 2.89 (m, 2H), 3.62 (m,
1H), 3.86 (s, 3H), 3.88 (s, 3H), 4.09 (m, 1H), 6.40 (br s, 0.5H),
6.43 (br s, 0.5H), 6.63 (s, 1H), 6.77 (s, 1H). 13C NMR: δ 11.58,
11.74, 16.94, 26.81, 27.12, 28.47, 37.28, 37.65, 41.28, 43.64, 56.06,
56.18, 109.91, 111.73, 118.08, 120.53, 126.03, 148.82, 149.71,
175.71. Anal. Calcd for C17H22N2O3: C, 67.53; H, 7.33. Found:
C, 67.43; H, 7.28. X-ray crystallography (see Supporting Informa-
tion, Figure S17) demonstrated that this was a 1:1 mixture of
diastereomers.
(1S)-2-(l-Menthoxycarbonyl)-l-cyano-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline [(S)-19]. From 6,7-dimethoxy-3,4-dihy-
droisoquinoline (17)25 and l-menthyl chloroformate, the crude solid
was treated with hexanes and ethanol until it dissolved. White
crystals formed immediately. The suspension was filtered to afford
a yellowish-white solid (51% yield), which was recrystallized twice
from ethanol to give colorless crystals of (S)-19. mp 185-187 °C.
[R]D25 ) -152.3 (c ) 1.79, CHCl3). IR (KBr): ν 2232, 1721 cm-l.
1H NMR: δ 0.90 (br m, 10H), 1.11 (m, 2H), 1.48 (br m, 2H), 1.69
(br d, J ) 11 Hz, 2H), 2.04 (br m, 2H), 2.73 (d, J ) 16 Hz, 1H),
2.89 (br m, 1H), 3.33 (br m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 4.21
(m, 1H), 4.68 (m, 1H), 5.81 (br s, 0.5H), 6.04 (br s, 0.5H), 6.64 (s,
1H), 6.75 (s, 1H). 13C NMR: δ 16.6, 20.8, 22.0, 23.7, 26.6, 27.7,
31.4, 34.3, 39.6, 41.4, 46.1, 47.5, 56.1, 56.2, 109.6, 111.9, 118.2,
126.8, 148.6, 149.7 (20 peaks; theory, 22). Anal. Calcd for
C23H32N2O4: C, 68.97; H, 8.05. Found: C, 68.73; H, 8.06. The
structure was established by X-ray crystallography (see Supporting
Information, Figure S21) and diastereomeric purity was confirmed
by HPLC (see Supporting Information, Figure S18).
1
H) cm-1. H NMR (CDCl3): δ 0.98 (s, 9H), 4.57 (d, J ) 7 Hz,
1H), 5.3 (d, J ) 7 Hz, 1H), 7.50-7.70 (m, 3H), 7.83 (d, J ) 8 Hz,
1H), 8.15 (d, J ) 8 Hz, 1H), 8.50 (d, J ) 8 Hz, 1H). Anal. Calcd
for C14H17NO: C, 78.10; H, 7.98; N, 6.51. Found: C, 77.97; H,
7.98; N, 6.34.
R-(+)-1-Isoquinolyl tert-Butyl Carbinol [(R)-16]. Hydrolysis
of R-(+)-1-isoquinolyl tert-butyl d-menthyl carbonate ((R)-13)
25
similarly produced (70%) (R)-16, with mp 100-101 °C and [R]D
) +68.9 (c ) 1.00, CH2Cl2). The optical purity as measured by
the use of quinine as outlined above was 98%. Spectral data of the
pure (+)-enantiomer were identical to those of the racemate and
the (-)-enantiomer (S)-16.
1-Methyl-2-(l-menthoxycarbonyl)-1,2-dihydroisoquinaldoni-
trile (22a). A glassy material that would not crystallize was obtained
1
in 92% yield. By both H NMR spectroscopy and HPLC (99:1
(1R)-2-(l-Menthoxycarbonyl)-l-cyano-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline [(R)-19]. The mother liquor from the
recrystallizations above yielded crystals (26%), which from ethanol
produced fine needle shaped crystals of (R)-19. mp 140-142 °C.
[R]D +49.9° (c ) 0.680, CHCl3). IR (KBr): ν 2235, 1693 cm-l.
1H NMR: δ 0.89 (br m, 12H), 1.45 (br m, 2H), 1.66 (br d, J ) 11
Hz, 2H), 2.08 (br m, 2H), 2.71 (m, 1H), 2.84 (br m, 1H), 3.31 (br
m, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 4.21 (m, 1H), 4.64 (m, 1H),
hexanes/isopropanol, flow rate 1 mL/min, see Supporting Informa-
tion, Figure S11) the product was shown to be comprised of equal
1
amounts of the two possible diastereomers. H NMR (CDCl3) δ
0.70-2.2 (m, 21 H, including a sharp singlet @ 1.91 ppm), 4.88
(m, 1H), 5.69 (d, J ) 8 Hz, 0.5H), 5.71 (d, J ) 8 Hz, 0.5H), 6.89
(d, J ) 8 Hz, 1H), 7.00 (m, 1H), 7.26 (m, 2H), 7.59 (m, 1H). FAB
MS (NBA-PEG) m/z: 352 (M+, 32%), 327 [(M + H - CN)+,
100%]. HRMS-FAB (NBA-PEG) m/z: 352.2145 (calcd for M+
352.2152).
(25) (a) Haworth, R. D. J. Chem. Soc. 1927, 2281-2284. (b) Whaley,
W. M.; Meadow, M. J. Chem. Soc. 1953, 1067-1070. (c) Popp, F. D.;
McEwen, W. E. J. Am. Chem. Soc. 1957, 79, 3773-3777. (d) Openshaw,
H. T.; Whittaker, N. J. Chem. Soc. 1963, 1461-1471. (e) Whaley, W. M.;
Govindachari, T. R. Org. React. 1969, 6, 74-150. (f) Warrener, R. N.;
Liu, L.; Russell, R. A. Tetrahedron 1998, 54, 7485-74960.
1-Methyl-2-cholesteryloxycarbonyl-1,2-dihydroisoquinaldoni-
trile (23a). Starting from pure diastereomer (S)-11 only ∼15%
1
conversion was obtained after 5 h at -40 °C. By both H NMR
spectroscopy and HPLC (Pirkle phenylglycine column, 99:1 hex-
anes/isopropanol, flow rate 1 mL/min, see Supporting Information,
5768 J. Org. Chem., Vol. 72, No. 15, 2007

Reissert Compounds Bearing Chiral Substituents
5.86 (br s, 0.5H), 6.03 (br s, 0.5H), 6.62 (s, 1H), 6.74 (s, 1H). 13
C
Supporting Information, Figure S26) demonstrated that this was a
1:1 mixture of the two diastereomers.
NMR: δ 16.5, 20.7, 21.9, 23.6, 26.5, 27.7, 31.4, 34.2, 39.5, 41.4,
45.9, 46.0, 47.4, 56.0, 56.1, 109.6, 111.8, 118.1, 126.7, 148.5, 149.6
(21 peaks; theory, 22). Anal. Calcd for C23H32N2O4: C, 68.97; H,
8.05; Found: C, 68.78; H, 8.13. Diastereomeric purity was
established by HPLC (see Supporting Information, Figure S18).
2-(8′-Phenyl-l-menthoxycarbonyl)-1-cyano-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (20). The crude light yellow wax
(80%) from 6,7-dimethoxy-3,4-dihydroisoquinoline (17)25 and
8-phenyl-l-menthyl chloroformate (see Supporting Information) was
examined by normal phase HPLC using a mixed solvent system of
10% ethyl acetate in hexanes, affording baseline separation of two
peaks at retention times of 11.7 and 12.5 min with relative peak
areas 20:80, respectively (see Supporting Information, Figure S22).
Attempts to recrystallize the solid failed. The material was purified
by flash column chromatography using 40% ethyl acetate in hexanes
to give a colorless amorphous solid that exhibited a phase-transition
1-Methyl-2-(l-menthoxycarbonyl)-l-cyano-1,2,3,4-tetrahydro-
6,7-dimethoxyisoquinoline (25a). General Alkylation Procedure
with NaH/DMF. To a stirred solution of (S)-19 (0.50 g, 1.3 mmol)
in DMF (40 mL) at 0 °C was added 60% NaH (0.050 g, 1.3 mmol).
The solution was stirred for 5 min. Iodomethane (0.19 g, 1.3 mmol)
was added via syringe and stirring continued at rt for 14 h. The
reaction mixture was poured into ice H2O (400 mL) and filtered to
give 0.43 g (83% yield) of white solid, which was recrystallized
25
from hexanes to afford a colorless powder. mp 110-114 °C. [R]D
) -52.3 (c ) 12.7, CHCl3). IR (KBr): ν 2234, 1705 cm-1. H
1
NMR (toluene-d8): δ 0.81 (d, J ) 6 Hz, 1.92H), 0.82 (d, J ) 6
Hz, 1.08H), 0.93 (d, J ) 7 Hz, 1.08H), 0.95 (d, J ) 7 Hz, 1.92H),
0.96 (d, J ) 7 Hz, 1.08H), 1.00 (d, J ) 7 Hz, 1.92H), 1.24 (m,
3H), 1.53 (m, 3H), 1.87 (s, 1.92H), 1.90 (s, 1.08H), 2.11 (m, 2H),
2.31 (m, 3H), 3.36 (s, 3H), 3.40 (s, 3H), 3.85 (t, J ) 6 Hz, 2H),
5.02 (m, 1H), 6.15 (s, 1H), 7.01 (s, 1H). 13C NMR (CDCl3): δ
16.3, 20.8, 21.9, 23.5, 26.3, 26.5, 28.9, 29.3, 29.7, 31.4, 34.2, 40.8,
41.0, 41.1, 41.4, 47.2, 54.6, 56.0, 56.2, 110.1, 111.0, 121.1, 126.4,
127.1, 148.5, 149.0, 154.8 (27 peaks; theory, 24 for each diaste-
reomer). Anal. Calcd for C24H34N2O4: C, 69.54; H, 8.27. Found:
C, 69.60; H, 8.31. The integration ratio of the two 1-methyl signals
at 1.90 and 1.87 ppm in the NMR spectrum of the crude product
in toluene-d8 was 36:64 (see Supporting Information, Figure S27).
1-Isopropyl-2-(l-menthoxycarbonyl)-1-cyano-6,7-dimethoxy-
1,2,3,4-tetrahydroiso-quinoline (25b). (S)-19 with 2-iodopropane
(NaH, DMF, 0 °C) gave a quantitative yield of a colorless solid,
which was recrystallized twice from ethanol. mp 132-134 °C.
[R]D25 ) -46.2° (c ) 15.6, CH2Cl2). IR (KBr): ν 2242, 1700 cm-l;
1H NMR: δ 0.63 (dd, J ) 3.3, 6.8 Hz, 3H), 0.81 (dd, J ) 0.9, 6.9
Hz, 3H), 0.91 (m, 6H), 1.08 (dd, J ) 2.9, 6.9 Hz, 6H), 1.47 (m,
2H), 1.69 (d, J ) 11.5 Hz, 2H), 1.90 (m, 1H), 2.13 (m, 1H), 2.64
(d, J ) 15.7 Hz, 1H), 2.88 (m, 1H), 3.20 (m, 2H), 3.89 (s, 6H),
4.25 (m, 1H), 4.75 (m, 1H), 6.63 (s 1H), 7.05 (d, J ) 2.4 Hz, 1H),
13C NMR: δ 16.1, 16.5, 18.9, 20.7, 22.0, 23.6, 26.6, 29.1, 31.5,
34.3, 36.7, 41.3, 41.9, 47.5, 55.9, 56.2, 63.2, 63.4, 111.0, 112.3,
119.8, 122.0, 128.4, 147.2, 149.0, 155.0. Anal. Calcd for
C26H30N2O4: C, 70.56; H, 8.65. Found: C, 70.62; H, 8.70. The
X-ray structure (see Supporting Information, Figure S28) revealed
this to be a 1:1 mixture of the two diastereomers.
25
at 70 °C. [R]D ) -70.5 (c ) 0.440, CHCl3). IR (KBr): ν 2234,
1
2254, 1698 cm-1. H NMR: δ 0.85 (m, 6H), 1.20 (m, 6H), 1.49
(m, 1H), 1.72 (m, 1H), 2.00 (m, 2H), 2.59 (m, 2H), 3.00 (m, 0.5H),
3.28 (m, 0.5H), 3.85 (m, 7H), 4.18 (m, 0.5H), 4.87 (m, 1H), 5.91
(m, 0.5H), 6.42 (m, 1H), 6.59, (m, 1H), 6.92 (t, J ) 8 Hz, 1H),
1
7.14 (m, 1H), 7.28 (m, 4H). The H NMR spectrum revealed the
presence of ethyl acetate. 13C NMR: δ 13.9, 20.9, 21.6, 22.5, 26.2,
26.8, 27.4, 27.9, 28.9, 29.9, 30.8, 31.3, 31.4, 34.5, 38.9, 39.1, 39.2,
41.9, 42.3, 44.8, 45.5, 45.8, 50.5, 50.9, 55.9, 56.0, 109.6, 110.1,
111.4, 118.1, 119.4, 120.2, 124.8, 125.2, 126.6, 127.3, 127.8, 128.1,
148.4, 149.2, 149.6, 152.6, 153.3. LR EIMS m/z: 476 (M+), 450
(M - CN)+, 380 (M - C7H12)+, 357 [M - C6H5C(CH3)2]+, 262
{100%, [M - C6H5C(CH3)2 - C7H8]+}, 245, 237, 217, 190, 176,
149, 119 {100%, [(C6H5C(CH3)2]+}, 105 [100%, (C8H9)+], 91
(100%), 85, 79, 71, 65, 55. Anal. Calcd for C29H36N2O4‚0.50(CH3-
COOC2H5): C, 71.50; H, 7.74; N, 5.38; Found: C, 71.06; H, 7.55;
N, 5.54.
2-[(+)-10-Camphorsulfonyl]-1-cyano-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (21). 6,7-Dimethoxy-3,4-dihydroisoquino-
line (17)25 and (+)-10-camphorsulfonyl chloride produced a peach
colored solid (66%), which was recrystallized from ethanol three
times to afford colorless, needle shaped crystals. mp 193-194 °C.
[R]D25 ) +24.9 (c ) 0.447, CHCl3). IR (KBr): ν 2233, 1748, 1149
cm-1. 1H NMR: δ 0.91 (d, J ) 7 Hz, 3H), 1.14 (d, J ) 7 Hz, 3H),
1.46 (m, 1H), 1.78 (m, 1H), 2.00 (d, 1H), 2.09 (m, 2H), 2.45 (m,
2H), 2.79 (m, 1H), 3.01 (m, 2H), 3.45 (m, 1H), 3.59 (m, 1H), 3.87
(s, 6H), 4.12 (m, 1H), 5.80 (d, J ) 7 Hz, 1H), 6.64 (d, J ) 8 Hz,
1H), 6.70 (d, J ) 8 Hz, 1H). 13C NMR: δ 19.9, 20.0, 25.3, 25.4,
27.0, 27.2, 28.0, 28.2, 41.2, 42.8, 43.3, 46.9, 47.8, 48.1, 48.3, 49.2,
56.2, 56.3, 58.4, 58.6, 109.4, 112.1, 117.5, 117.7, 119.3, 119.7,
125.8, 148.8, 150.0, 214.1. Anal. Calcd for C22H28N2O5S: C, 61.09;
H, 6.52; N, 6.48; S, 7.42. Found: C, 61.16; H, 6.50; N, 6.54; S,
7.49.
1-Methyl-2-[(S)-R-methylbutyryl]-1-cyano-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (24a). To a stirred solution of 18
(0.20 g, 0.66 mmol) in 10 mL of dry THF under argon at -78 °C
was added n-butyllithium (0.66 mmol). The light yellow mixture
was stirred at -78 °C for 15 min. Iodomethane (0.14 g, 1.0 mmol)
was added via syringe. The mixture was stirred at -78 °C for 3 h,
during which time the color slowly faded. The mixture was allowed
to warm to rt. CH2Cl2 (50 mL) was added to the mixture, and the
solution was washed with brine (five times) and dried over anhyd
Na2SO4. The solvent was removed in vacuo to give 0.19 g (90%)
of a glassy solid, which was recrystallized from ethanol to afford
large chunky crystals. mp 139-142 °C. [R]D25 ) +34.1 (c ) 0.507,
CHCl3). IR (KBr): ν 2237, 1661 cm-1. 1H NMR: δ 0.92 (m, 3H),
1.17 (m, 3H), 1.48 (m, 1H), 1.79 (m, 1H), 1.92 (s, 1.5H), 1.93 (s,
1.5H), 2.71 (m, 1H), 2.83 (m, 2H), 3.68 (m, 2H), 3.87 (s, 3H),
3.91 (s, 3H), 6.61 (s, 1H), 7.05 (s, 1H). 13C NMR: δ 11.7, 16.8,
26.8, 27.1, 28.1, 28.5, 29.4, 38.7, 42.2, 56.1, 56.2, 110.1, 110.9,
126.0, 148.8, 149.1, 176.2. Anal. Calcd for C18H24N2O3: C, 68.33;
H, 7.65. Found: C, 68.38; H, 7.69. X-ray crystallography (see
l-Benzyl-2-(l-menthoxycarbonyl)-l-cyano-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (25c). (S)-19 and benzyl iodide (NaH,
DMF, rt) yielded (89%) a white powder, which was recrystallized
25
twice from hexanes as colorless needles. mp 109-111 °C. [R]D
) -41.7 (c ) 7.60, CHCl3). IR (KBr): ν 2231, 1696 cm-1. H
1
NMR: δ 0.97 (m, 12H), 1.13 (m, 1H), 1.54 (m, 2H), 1.72 (d, J )
11 Hz, 2H), 2.03 (br s, 1H), 2.22 (q, J ) 13 Hz, 2H), 3.15 (t, J )
11 Hz, 1H), 3.31 (dd, J ) 13, 19 Hz, 1H), 3.70 (m, 1H), 3.86 (m,
6H), 4.10 (br, 1H), 4.83 (br, 1H), 6.42 (d, J ) 4 Hz, 1H), 6.59 (dd,
J ) 7, 4 Hz, 2H), 6.94 (br s, 1H), 7.07 (dd, J ) 8, 14 Hz, 2H),
7.18 (m, 1H). 13C NMR: δ 16.4, 20.8, 22.0, 23.5, 23.6, 26.4, 26.7,
28.0, 31.6, 34.4, 41.4, 41.5, 41.6, 46.8, 47.3, 47.4, 56.0, 56.2, 58.8,
59.1, 110.5, 110.6, 110.8, 120.1, 120.4, 124.2, 127.4, 127.7, 127.8,
128.5, 128.7, 130.9, 133.8, 148.1, 148.2, 149.1, 154.8. Anal. Calcd
for C30H38N2O4: C, 73.44; H, 7.81. Found: C, 73.45; H, 7.85.
1-Methyl-2-(8′-phenyl-l-menthoxycarbonyl)-1-cyano-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline (26a). 20 and io-
domethane (NaH, DMF, rt) afforded a quantitative yield of a yellow
oil; flash chromatography using 30% ethyl acetate in hexanes as
the eluent yielded a colorless oil. IR (neat): ν 2235, 2254, 1698,
1
1693 cm-1. H NMR: δ 0.85 (d, J ) 7, 3H), 1.05 (m, 2H), 1.19
(m, 4H), 1.36 (d, J ) 7 Hz, 3H), 1.48 (m, 1H), 1.70 (m, 2H), 1.87
(d, J ) 7 Hz, 3H), 1.95 (m, 1H), 2.10 (m, 1H), 2.47 (m, 2.5H),
2.50 (m, 0.5H), 2.88 (m, 0.5H), 3.08 (m, 0.5H), 3.87 (m, 6H), 4.92
(m, 1H), 6.53 (d, J ) 8 Hz, 1H), 6.98 (d, J ) 8 Hz, 1H), 7.08 (m,
1H), 7.31 (m, 4H). 13C NMR: δ 21.7, 23.2, 24.5, 26.5, 28.5, 28.7,
29.2, 29.5, 31.3, 34.6, 39.4, 39.6, 39.9, 40.1, 42.3, 50.5, 50.7, 54.5,
55.9, 56.2, 109.9, 110.9, 120.9, 124.8, 125.2, 125.3, 126.33, 126.9,
J. Org. Chem, Vol. 72, No. 15, 2007 5769

Gibson et al.
127.1, 127.8, 127.9, 128.0, 148.4, 149.0, 152.6, 153.7, 153.9. LR
EIMS m/z: 490.2 (M+), 475.2 (M - CH3)+, 464.3 (M - CN)+,
394.2 (M - C7H12)+, 371.2 [M - C6H5C(CH3)2]+, 276.1 [M -
C6H5C(CH3)2 - C7H8 ]+, 261.2 [M - C6H5C(CH3)2 - C7H9 -
CH3]+, 248.1, 217.1, 119.1 {100%, [(C6H5C(CH3)2]+}, 105.1
(C8H9)+, 91.0 (C7H7)+. HR EIMS m/z: calcd for C30H38N2O4 (M+),
490.2832; found, 490.2825 (see Supporting Information, Figure
S30). The integration of the two 1-methyl signals at 1.90 and 1.87
ppm in toluene-d8 was 67:33, respectively (see Supporting Informa-
tion, Figure S29).
using ethyl acetate and then by recrystallization from ethyl acetate/
hexanes, affording colorless crystals of 28. mp 85-90 °C (lit.26a
1
mp 89-91 °C, 90-91 °C26b). IR (KBr): ν 1507, 1254 cm-1. H
NMR: δ 4.02 (s, 6H), 7.05 (s, 1H), 7.18 (s, 1H), 7.49 (d, J ) 8
Hz, 1H), 8.37 (d, J ) 8 Hz, 1H), 9.03 (s, 1H). 13C NMR: δ 55.5,
55.8, 104.1, 104.9, 118.8, 124.4, 132.1, 144.4, 149.4, 149.9, 152.7.
Acknowledgment. This work was partially supported by a
Biomedical Research Support Grant, Public Health Service via
Virginia Polytechnic Institute and State University and the
Department of Chemistry.
Attempted Alkylation of 2-[(+)-10-Camphorsulfonyl]-1-cy-
ano-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (21). 21 and
iodomethane (NaH, DMF, -40 °C for anion formation and rt for
alkylation) gave (40%) fine white needles of 27. mp 148-149 °C.
Supporting Information Available: General experimental and
synthetic procedures (including known starting materials); pertinent
1H NMR spectra, HPLC traces, and X-ray structures. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
IR (KBr): ν 1609, 1286 cm-1. H NMR: δ 2.73 (t, J ) 7 Hz,
2H), 3.93 (m, 8H), 6.68 (s, 1H), 7.12 (s, 1H). 13C NMR: δ 24.2,
48.7, 56.2, 56.3, 109.4, 110.6, 114.6, 119.1, 130.0, 145.9, 148.5,
153.1. Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.95.
Found: C, 66.64; H, 5.61; N, 12.98.
JO070786K
(26) (a) Spath, E.; Polgar, N. Monatsh. Chem. 1929, 51, 190-204. (b)
Birch, A. J.; Jackson, A. H.; Shannon, P. V. R. J. Chem. Soc., Perkin Trans.
1 1974, 19, 2185-2190.
Alternatively, treatment of 21 alone with NaH/DMF at rt yielded
a yellow oil (60%), which was purified by flash chromatography
5770 J. Org. Chem., Vol. 72, No. 15, 2007