Chlorination/cyclodehydration of amino alcohols with SOCl2: An old reaction revisited

Article abstract of DOI:10.1021/jo701877h

(Chemical Equation Presented) A simple, one-pot preparation of cyclic amines via efficient chlorination of amino alcohols with use of SOCl₂ has been developed. This approach obviates the need for the classical N-protection/O-activation/cyclization/deprotection sequence commonly employed for this type of transformation. The reaction pathways and the general scope of this method have also been investigated.

Full text of DOI:10.1021/jo701877h

amines include (1) redox organometallic reagents4 such as RuH2-
(PPh3)4 and RhH(PPh3)4, (2) exposure to acidic conditions5 by
generating a corresponding cation intermediate with suitable
substrates, (3) phosphorus-assisted Mitsunobu reaction,6 and (4)
direct activation3 including halogenation to produce a halo-amine
intermediate. For example, the use of the Appel reaction and
its variants is widely applied,7 although there are drawbacks in
large-scale production. Surprisingly, direct chlorination of amino
alcohol free bases with SOCl2, which was discovered several
decades ago, has not been well studied;8,9 its application is
underutilized due to the expected competition10 between N- and
O-sulfinylation, and subsequent “inevitable” side reactions. Low
yields are typically an issue for this reaction.11
Chlorination/Cyclodehydration of Amino
Alcohols with SOCl2: An Old Reaction Revisited
Feng Xu,* Bryon Simmons, Robert A. Reamer,
Edward Corley, Jerry Murry, and David Tschaen
Department of Process Research, Merck Research Laboratory,
Rahway, New Jersey 07065
feng_xu@merck.com
ReceiVed September 1, 2007
Recently during our asymmetric syntheses of (+)-bicifadine
(1a) and DOV21947 (1b) (Scheme 1),12 we developed a
practical direct chlorination of amino alcohol 2 with SOCl2 to
prepare amino chloride 3, which immediately cyclized to
3-azabicyclo[3.1.0]hexanes 1 upon pH adjustment during aque-
ous workup in nearly quantitative yield. Herein, we further detail
our results including the reaction scope and mechanistic insights
into the reaction pathway as revealed by NMR spectroscopic
studies.
The formation of chlorosulfinyl ester intermediates during
the chlorination of alcohols with SOCl2 is well recognized.
Isolation of the chlorosulfinyl ester has been reported.13 It is
also well-known that treatment of 1,2-amino alcohols with
SOCl2 in the presence of bases gives cyclic sulfamides, which
are the products of subsequent intramolecular O- or N-
sulfinylation of the initially formed chlorosulfinyl esters/
amides.14 After surveying the literature15,16 related to chlorination
A simple, one-pot preparation of cyclic amines via efficient
chlorination of amino alcohols with use of SOCl2 has been
developed. This approach obviates the need for the classical
N-protection/O-activation/cyclization/deprotection sequence
commonly employed for this type of transformation. The
reaction pathways and the general scope of this method have
also been investigated.
Cyclodehydration of amino alcohols (eq 1) is an important
and useful transformation for the preparation of nitrogen
heterocycles. Many cyclodehydration methodologies1,2 have
been developed; however, classical indirect cyclodehydration
of amino alcohols typically involves a tedious sequence of
protection/activation/cyclization/deprotection. Although com-
monly implemented,1,2 these indirect approaches require multiple
chemical steps that reduce the overall efficiency of the
transformation. The commonly used direct cyclodehydration
methods3-7 of amino alcohols to the corresponding cyclic
(6) For recent reviews, see: (a) Hughes, D. L. Org. Prep. Proc. Int.
1996, 28, 127. (b) Hughes, D. L. Org. React. 1992, 42, 335.(c) Mitsunobu,
O. Synthesis 1981, 1.
(7) For reviews, see: (a) Castro, B. R. Org. React. 1983, 29, 1. (b) Appel,
R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801.
(8) For recent reviews about SOCl2, see: (a) El-Sakka, I. A.; Hassan,
N. A. J. Sulfur Chem. 2005, 26, 33. (b) Wirth, D. D. In Encyclopedia of
Reagents for Organic Synthesis; Paquette, L. A., Ed.; John Wiley & Sons:
New York, 1995; p 4873. (c) Oka, K. Synthesis 1981, 661.
(9) Chlorination of alcohols, excluding amino alcohols, with SOCl2 is
thoroughly studied in terms of both mechanism and practical applications.8
(10) For example, see: Pilkington, M.; Wallis, J. D. Chem. Commun.
1993, 1857.
(11) For examples of chlorination of amino alcohol salts, see: (a) Back,
T. G.; Nakajima, K. J. Org. Chem. 2000, 65, 4543. (b) Bubnov, Y. N.;
Zykov, A. Y.; Ignatenko, A. V.; Mikhailovsky, A. G.; Shklyaev, Y. V.;
Shklyaev, V. S. IzV. Akad. Nauk., Ser. Khim. 1996, 935. (c) Dobler, M.;
Beerli, R.; Weissmahr, W. K.; Borschberg, H.-J. Tetrahedron: Asymmetry
1992, 11, 1411. (d) Ko´bor, J.; Fu¨lo¨p, F.; Berna´th, G.; Soha´r, P. Tetrahedron
1987, 43, 1887. (e) Ba¨ckvall, J. E.; Renko, Z. D.; Bystro¨m, S. E. Tetrahedron
Lett. 1987, 28, 4199. (f) Piper, J. R.; Johnston, T. P. J. Org. Chem. 1963,
28, 981. (g) Norton, T. R.; Seibert, R. A.; Benson, A. A.; Bergstrom, F. W.
J. Am. Chem. Soc. 1946, 68, 1572.
(1) For recent reviews, see: (a) Buffat, M. G. P. Tetrahedron 2004, 60,
1701. (b) Larock, R. C. ComprehensiVe Organic Transformations, 2nd ed.;
Wiley-VCH: New York, 1999; pp 689-702 and 779-784.
(2) For recent examples and applications, see: (a) Smith, A. B., III; Kim,
D.-S. J. Org. Chem. 2006, 71, 2547. (b) Trost, B. M.; Tang, W.; Toste, F.
D. J. Am. Chem. Soc. 2005, 127, 14785. (c) Pyne, S. G.; Davis, A. S.;
Gates, N. J.; Hartley, J. P.; Lindsay, K. B.; Machan, T.; Tang, M. Synlett
2004, 2670. (d) Kan, T.; Kobayshi, H.; Fukuyama, T. Synlett 2002, 697.
(e) Ina, H.; Kibayashi, C. J. Org. Chem. 1993, 58, 52. (f) Burgess, K.;
Chaplin, D. A.; Henderson, I.; Pan, Y. T.; Elbein, A. D. J. Org. Chem.
1992, 57, 1103. (g) Schink, H. E.; Pettersson, H.; Ba¨ckvall, J.-E. J. Org.
Chem. 1991, 56, 2769.
(3) For recent applications of direct cyclodehydration methods, see: (a)
de Figueiredo, R. M.; Fro¨hlich, R.; Christmann, M. J. Org. Chem. 2006,
71, 4147. (b) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2006, 128, 9646.
(c) Pulz, R.; Al-Harrasi, A.; Reissig, H.-U. Org. Lett. 2002, 4, 2353 and
references cited therein.
(4) (a) Nota, T.; Murahashi, S.-I. Synlett 1991, 693. (b) Murahashi, S.-
I.; Kondo, K.; Hakata, T. Tetrahedron Lett. 1982, 23, 229. (c) Grigg, R.;
Mitchell, T. R. B.; Sutthivaiyakit S.; Tongpenyai, N. Chem. Commun. 1981,
611.
(5) For examples, see: (a) Tanaka, H.; Murakami, Y.; Aizawa, T.; Torii,
S. Bull. Chem. Soc. Jpn. 1989, 62, 3742. (b) Papageorgiou, C.; Borer, X.
HelV. Chim. Acta 1988, 71, 1079.
(12) Xu, F.; Murry, J. A.; Simmons, B.; Corley, E.; Fitch, K.; Karady,
S.; Tschaen, D. Org. Lett. 2006, 8, 3885.
(13) Gerrard, W. J. Chem. Soc. 1940, 218
(14) For examples, see: (a) Lu, B. Z.; Jin, F.; Zhang, Y.; Wu, X.; Wald,
S. A.; Senanayake, C. H. Org. Lett. 2005, 7, 1465. (b) Benson, S. C.; Snyder,
J. K. Tetrahedron Lett. 1991, 32, 5885. (c) Lowe, G.; Reed, M. A.
Tetrahedron: Asymmetry 1990, 1, 885.
10.1021/jo701877h CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/05/2007
312
J. Org. Chem. 2008, 73, 312-315

SCHEME 1. Preparation of DOV 21947 and (+) Bicifadinea
SCHEME 2. Reaction Pathways for Chlorination of 4 with
SOCl2
a Reagents and conditions: (a) 1.2 equiv of SOCl2, i-PrOAc, 25 °C; (b)
aq NaOH, pH 8.5-9.5.
of amino alcohol free base with SOCl2, we noticed that SOCl2
was typically added to the solution of substrates in the presence
or absence of bases. The reaction notoriously gave poor yields.
In fact, we also obtained 3 in poor yield when SOCl2 was added
to a solution of free base 2 in i-PrOAc or (MeOCH2)2 slowly.
The reaction turned dark red and formed gummy solids, which
could be observed after about 0.3 equiv of SOCl2 were
introduced. HPLC analysis of the reaction revealed that many
undesired byproducts were formed.
However, we reasoned that a clean cyclodehydration trans-
formation could still be achieved by utilizing SOCl2 as an OH
activation/chlorination reagent if the nucleophilic amine species
could be “protected/quenched” through rapid protonation and/
or N-sulfinylation under acidic reaction conditions. Thus, the
sulfinamide byproducts formed via nucleophilic amine attacking
the N- or O-sulfinylated species could be minimized.17
To test this hypothesis, the HCl salt 2b was treated with
SOCl2 in i-PrOAc. The formation of byproducts was signifi-
cantly suppressed since the nucleophilic NH2 was protonated.
However, incomplete chlorination reaction was observed due
to the poor solubility of the corresponding HCl amine salts,
which precipitated from the reaction mixture. Interestingly, a
clear homogeneous reaction solution was obtained,18 if an
inVerse addition of a solution of the free base 2b in i-PrOAc to
SOCl2 was carried out. Under these inverse addition conditions,
complete conversion of 2b to the corresponding chloride 3b
was observed by HPLC analysis.
spectroscopy (Scheme 2). When SOCl2 (1.5 equiv) was quickly
mixed with a solution of the cis amino alcohol 412 in d8-THF
at 0 °C, the formation of the chlorosulfinate ester and amide
was immediately observed. As expected, 4 was partially
converted to the chlorosulfinylate ester 6 while the NH2 was
protonated by the HCl formed during the reaction right after
SOCl2 was introduced. Although it was expected that the initial
contact of SOCl2 with amine 4 under the above quick mixing
conditions was not well controlled and would also result in the
formation of the corresponding bissulfinylated ester 7, the fact
of the formation of a fair amount of bissulfinylated ester 7 under
acidic conditions indicated that the O-sulfinylation is competi-
tively faster than the formation of intermolecular sulfamide
byproducts (RNHS(O)OR′) via subsequently coupling between
the free OH/NH2 with the corresponding monosulfinylated
intermediates (vide infra).
The structures of 6-9 were unambiguously elucidated by
applying various NMR techniques (1-D TOCSY, HMQC, and
13C NMR). The proton spin-spin coupling networks were easily
identified by 1-D TOCSY experiments and these protons could
then correlate with 13C via 2-D HMQC experiments. The 13C
NMR data for -CH2OS(O)Cl (69.4 and 69.2 ppm for interme-
diates 6 and 7, respectively) and -CH2Cl (46.4 and 46.5 ppm
for intermediates 9 and 8, respectively) further supported the
formation of these intermediates.
To better understand the difference between the two modes
of addition, we studied the reaction using in situ NMR
(15) For examples of chlorination of amino alcohols with SOCl2 in the
presence of bases, see: (a) Muratake, H.; Natsume, M. Tetrahedron Lett.
2002, 43, 2913. (b) Howarth, N. M.; Malpass, J. R.; Smith, C. R.
Tetrahedron 1998, 54, 10899. (c) Bosch, J.; Mestre, E.; Bonjoch, J.; Lo´pez,
F.; Granados, R. Heterocycles 1984, 22, 767. (d) Mousseron, M.; Winternitz,
F.; Mousseron-Canet, M. Bull. Soc. Chim. Fr. 1953, 737.
(16) For examples of chlorination of amino alcohols with SOCl2 in the
absence of bases by adding SOCl2 to amino alcohol solution, see: (a)
Gursky, M. E.; Ponomarev, V. A.; Pershin, D. G.; Bubnov, Y. N.; Antipin,
M. Y.; Lyssenko, K. A. Russ. Chem. Bull. 2002, 51, 1562. (b) Foubelo, F.;
Go´mez, C.; Gutie´rrez, A.; Yus, M. J. Heterocycl. Chem. 2000, 37, 1061.
(c) Howarth, N. M.; Malpass, J. R.; Smith, C. R. Tetrahedron 1998, 54,
10899. (d) Gursky, M. E.; Potapova, T. V.; Bubnov, Y. N. IzV. Akad. Nauk.,
Ser Khim. 1998, 1450. (e) Bubnov, Y. N.; Zykov, A. Y.; Ignatenko, A. V.;
Mikhailovsky, A. G.; Shklyaev, Y. V.; Shklyaev, V. S. IzV. Akad. Nauk.,
Ser Khim. 1996, 935. (f) Granier, C.; Guilard, R. Tetrahedron 1995, 51,
1197. (g) Grigg, R.; Santhakumar, V.; Sridharan, V.; Thornton-Pett, M.;
Brideg, A. W. Tetreahedron 1993, 49, 5177. (h) Takano, S.; Inomata, K.;
Sato, T.; Ogasawara, K. Chem. Commun. 1989, 1591. (i) Barbry, D.;
Couturier, D.; Ricart, G. Synthesis 1980, 387. (j) Sturm, P. A.; Cory, M.;
Henry, D. W. J. Med. Chem. 1977, 20, 1333. (k) Giacet, C.; Be´cue, G. C.
R. Acad. Sci., C 1967, 264, 103.
Conversion of the chlorosulfinate esters 6/7 to the corre-
sponding chlorides 9/8 was slow at 0 °C, as confirmed by NMR
studies. After the sample was aged (Figure 1, spectrum a) at 0
°C, chlorosulfinate intermediates, as expected, turned to a
mixture of 8/9 (Figure 1, spectrum d). However, further aging
of the reaction mixture at ambient temperature for several hours
resulted in 8 as the major product while 9 was partially
converted to 8 (Figure 1, spectrum f). Surprisingly, the sulfi-
+
nylation of the protonated NH3 group of 9 with ClS(O)OH,
which was liberated as the chlorosulfinate intermediates were
converted to the chloride intermediates, could still happen under
these acidic reaction conditions to form the sulfamic acid 8.
(17) It is known that the formation of sulfinamides from the correspond-
ing N- or O-sulfinylated species is accelerated in the presence of bases.8,14
(18) Although a slurry was obtained after prolonged agitation of the
reaction mixture at ambient temperature, the precipitation of the HCl salt,
which can be isolated and characterized, was believed to be a result of
solubility-driven equilibrium shift. See more discussion in the text.
+
The N-sulfinylation of the protonated NH3 with SOCl2/
ClSO2H was also unambiguously confirmed when the chlorina-
tion of 2b was carried out in the presence of SOCl2. After a
solution of 2b in d8-THF was added slowly to a solution of
J. Org. Chem, Vol. 73, No. 1, 2008 313

TABLE 1. Direct Chlorination/Cyclization of Amino Alcohols
FIGURE 1. NMR spectra of the reaction sequence in the chlorina-
tion of 4 in d8-THF. (a) 1H NMR spectrum at t ) 45 min at 0 °C, after
1.5 equiv of SOCl2 was added to a solution of 4 in one portion at 0 °C.
(b) TOCSY spectrum obtained by irradiating the solution from part a
at 1.81 ppm. (c) TOCSY spectrum obtained by irradiating the solution
1
form part a at 1.95 ppm. (d) H NMR spectrum at t ) 3.5 h at 0 °C.
(e) TOCSY spectrum obtained by irradiating the solution from part d
at 1.07 ppm. (f) 1H NMR spectrum at t ) 18 h at ambient temperature.
SCHEME 3. Chlorination of 2b with SOCl2
a Unless otherwise mentioned, the cyclization was carried out in the same
solvent as the chlorination. b Isolated yield. c Isolated as its HCl salt.
SOCl2 (1.2 equiv) in d8-THF, NMR studies (see the Supporting
Information, Figure S1) of the crude reaction mixture before
aqueous base quench clearly showed the complete formation
of the two products, protonated salt 3b and sulfamic intermediate
10, in about 3:2 ratio (Scheme 3).19 The observed ratio of
protonated salt 3b:10 clearly indicated that ClSO2H formed
during the reaction is responsible for the formation of 10, since
only 1.2 equiv of SOCl2 total was charged during the reaction.
Thus, a rational conclusion for the most desirable way to
run the reaction would be slow inVerse-addition of the amino
alcohol solution in an appropriate solvent to a solution of
SOCl2. The amino alcohol substrate would become instantly
protonated upon contact with adventitious HCl in the
SOCl2 solution or the HCl generated during the O-sulfinylation
step as well as the “inevitable” N-sulfinylation step. Because
the amino alcohol substrate is added slowly to keep a low
concentration of its protonated salt in the reaction mixture, the
protonated amino alcohol substrate would be expected to
react with excess SOCl2 before it crystallizes.18 Thus, complete
conversion could be achieved. In addition, the minor N-
sulfinylated intermediates (such as sulfamic chloride 7) that
could be formed “inevitably” by reacting with SOCl2 are also
preserved and further converted to the corresponding chlorides
(such as 8 and 10, X ) Cl) in the acidic inverse-addition reaction
media, because the nucleophilic amine species that could
react with these N-sulfinylated intermediates are either quenched
by HCl or converted to sulfamic acids with ClSO2H. Finally,
the formation of sulfamic chlorides/acids (such as 8 and 10)
is also believed to partially contribute to retaining a kinetically
homogeneous reaction solution during the inverse-addition of
amine substrate 2b to SOCl2 since they do not readily precipi-
tate from the reaction mixture like the HCl salt does (vide
supra).18,19
Building on these mechanistic insights, an optimal, one-pot
process for converting amino alcohols to the corresponding
cyclized products was developed. A solution of amino alcohol
2 in either i-PrOAc or (MeOCH2)2 was slowly added over 2 h
to a solution of SOCl2 in the same solvent at ambient
temperature. No sticky solids, discoloration, or significant
undesired side products were observed. The reaction mixture
was directly quenched with aqueous base after a complete
conversion was achieved. The trans chloride 3 was cyclized to
(19) In principle, protonation of amine moiety would attenuate nitrogen’s
reactivity and allow the hydroxyl group to react preferentially over
the ammonium group. If these protonated amine salts are soluble, a
good conversion can be achieved. However, the solubility of protonated
amino alcohols as well as their corresponding protonated amino chloride
salts in these solvents, which are compatible to SOCl2, would often
create an undesirable slurry-to-slurry reaction (even formation of a
gummy reaction mixture as mentioned above) accompanied by low
conversion. Similarly, we observed incomplete conversion when the HCl
salt 2 was treated with SOCl2 in solvents such as i-PrOAc, (MeOCH2)2,
and CHCl3.
(20) The formation of possible sulfamide intermediate I was not observed.
314 J. Org. Chem., Vol. 73, No. 1, 2008

1 immediately upon adjusting the pH to >8.5.20 The cyclized
pyrrolidine 1 was isolated in 95% yield following workup.21
To further explore the chlorination/cyclodeydration scope, a
variety of amino alcohols were examined. The results are
summarized in Table 1. In a typical experiment, a solution of
amino alcohol (ca. 0.2 M) in solvents such as (MeOCH2)2 or
i-PrOAc or CH2Cl2 was added over several hours to a solution
of SOCl2 (1.2 equiv, 0.2 M based on amino alcohol) in the same
solvent. We were gratified to observe that all of the amino
alcohols examined were cleanly and efficiently converted to the
corresponding amino chloride in nearly quantitative yield. Full
conversion to the desired chloride was observed within 5 h for
most examples; however, compounds 13 and 20 required heating
at 40 °C for several hours to achieve complete conversion to
the corresponding chloride, respectively.
For direct cyclodehydration transformation, the above crude
chloro amine intermediates were treated with base. The in-
tramolecular cyclization rate is dependent on the substrates, as
expected. Upon addition of excess alkaline aqueous base to the
reaction mixture, pyrrolidines 21, 22, and (()-crispine A 2322
(Table 1. entries 1-3) were formed instantaneously from the
corresponding 1,4-amino chlorides. Complete formation of
pyrrolidines 24 and 25 required thermal instigation over an
extended period (Table 1, entries 4 and 5). These slower rates
can be rationalized by the attenuated nucleophilicity of the
aniline nitrogen on 14 and the ring strain presumed to be present
in 15. The formation of piperidines 26-28 (Table 1, entries
6-8) was easily achieved after aging the corresponding 1,5-
amino chloride free bases for several hours at ambient temper-
ature. However, a cleaner cyclization to 28 could be obtained
by diluting the reaction solution to 0.01 M from 0.1 M before
the addition of aqueous base. Attempts to cyclize the readily
formed 1,2- and 1,3-chloroamines 29 and 30 even at elevated
temperatures resulted in complicated mixtures containing only
small amounts of desired cyclized product.23
into the reaction pathway. The general scope of this approach
and its practical efficiency were demonstrated on a wide variety
of amino alcohols.
Experimental Section
General Procedure. To a solution of SOCl2 (1.2-3 equiv) in a
solvent such as i-PrOAc or (MeOCH2)2 or CH2Cl2 (ca. 0.2 M) was
subsurface-added a solution of amino alcohol (1.0 equiv, ca. 0.2
M) in the same solvent dropwise over 1 h. The reaction mixture
was allowed to stir for additional 1-5 h, then quenched with a
base such as aqueous NaOH or Na3PO4. For these substrates
cyclized at ambient temperature, the separated organic layer was
washed with water and brine, and then dried over Na2SO4. Upon
concentration in vacuum, the product was purified on silica gel
column to give the desired product. For these substrates cyclized
at elevated temperature, the organic phase could be separated and
the corresponding chloride was then cyclized under the conditions
as specified in Table 1.
(1R,5S)-1-(4-Methylphenyl)-3-azabicyclo3,10hexane [(+)-Bici-
fadine, 1a]. To a solution of SOCl2 (4.08 mL, 55.85 mmol,) in
i-PrOAc (50 mL) was slowly subsurface-added a solution of amino
alcohol 2a (8.89 g, 46.54 mmol) in i-PrOAc (50 mL) at ambient
temperature over 1 h. After an additional 2 h, 5.0 N NaOH (45
mL) was added over 1 h while the batch temperature was
maintained at <30 °C with external cooling. The two-phase reaction
mixture was stirred for 1 h at ambient temperature to allow pH to
stabilize (usually to 8.5-9.0) with NaOH pH titration. The organic
phase was washed with water (2 × 20 mL). Concentrated HCl (4.0
mL) was added to the organic phase while the internal temperature
was kept <30 °C. The aqueous i-PrOAc was azeotropically
concentrated in vacuum to a final volume of ca. 50 mL. The solid
was filtered and washed with i-PrOAc (2 × 20 mL). Suction dry
1
gave 9.0 g of the desired HCl salt (92% isolated yield). H NMR
In summary, modifications to an “old” method for activating
OH have resulted in a simple process for the chlorination of
amino alcohols in the presence of SOCl2. This reaction has been
extended to cyclodehydration of amino alcohols in a practical
one-pot process. In situ NMR studies provided useful insights
(400 MHz, d4-MeOH): δ 7.17 (m, 4 H), 3.73 (d, J ) 11.4 Hz, 1
H), 3.66 (dd, J ) 3.8, 11.4 Hz, 1 H), 3.58 (d, J ) 11.4 Hz, 1 H),
3.51 (d, J ) 11.4 Hz, 1 H), 2.31 (s, 3 H), 2.10 (m, 1 H), 1.22 (t,
J ) 7.5 Hz, 1 H), 1.12 (t, J ) 5.4 Hz, 1 H). 13C NMR (100 MHz,
d4-MeOH): δ 138.3, 136.8, 130.6, 128.3, 52.3, 49.3, 32.3, 24.2,
21.2, 16.0. Anal. Calcd for C12H16ClN: C, 68.73; H, 7.69; N, 6.68.
Found: C, 68.52; H, 7.69; N, 6.64.
(21) This process was successfully and reproducibly carried out in 5 kg
scale with 1.2 equiv of SOCl2.
(22) 13 is commercially available. For leading references of the synthesis
of crispine A, see: (a) King, F. D. Tetrahedron 2007, 63, 2053. (b) Kno¨elker,
H.-J.; Agarwal, S. Tetrahedron Lett. 2005, 46, 1173.
(23) For examples of relative rates of cyclization as a function of ring
size, see: (a) Mandolini, L. AdV. Phys. Org. Chem. 1986, 22, 1. (b) Winnik,
M. A. Chem. ReV. 1981, 81, 491. (c) Galli, C.; Illuminati, G.; Mandolini,
L.; Tamborra, P. J. Am. Chem. Soc. 1977, 99, 2591.
Supporting Information Available: Experimental procedures
and spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO701877H
J. Org. Chem, Vol. 73, No. 1, 2008 315